Phenylcarbamate crystalline form and method for manufacturing the same

ABSTRACT

The present invention relates to crystalline forms of a phenyl carbamate derivative compound and compositions and uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part of U.S. application Ser. No. 17/837,929, filed on Jun. 10, 2022, which claims priority to Korean Patent Application No. 10-2021-0103371 filed on Aug. 5, 2021, the disclosures of which are incorporated herein by reference in their entirety.

BACKGROUND

Phenyl carbamate compounds are compounds known to have an effect on various neurological disorders including multiple sclerosis, Lou Gehrig's disease, epilepsy and central nervous system disorders, muscle diseases, stroke, psychiatric disorder and memory loss-related diseases. These compounds have excellent pharmacological effects on various diseases due to its high pharmacological activity, and have been developed and widely used as medicines due to low toxicity.

Among the phenyl carbamate compounds, (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101) is a material that is verified to be particularly effective in treatment or prevention of multiple sclerosis (Korean Patent No. 10-2014-0113919 A) or Lou Gehrig's disease (10-2014-0113918 A), and research is being attempted to synthesize various crystalline forms of the material such that they have more improved stability and can be used in various formulations.

BRIEF SUMMARY OF THE INVENTION

In embodiments, the present provides crystalline forms of a phenyl carbamate derivative compound, 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101).

In embodiments, the present disclosure provides a pharmaceutical composition comprising a crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101).

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the result of comparing XRPD patterns after 1,4-dioxane treatment (ED01748-009-001-00, Pattern 2) to form amorphous 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101).

FIG. 2 shows the result of comparing XRPD patterns after 1,4-dioxane treatment (ED01748-009-001-00, Pattern 2) and storing overnight (ED01748-009-005-00, Pattern 3) to form amorphous 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101).

FIG. 3 shows the result of comparing XRPD patterns after t-butanol treatment (ED01748-009-006-00, Pattern 1), treatment of t-butanol with water (ED01748-013-002-00, Pattern 1) to form amorphous 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101).

FIG. 4 shows the result of comparing XRPD patterns of a material (ED01748-013-002-00, Pattern 1) formed by treatment of a dichloromethane solution and evaporation of the solution to form amorphous 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101).

FIG. 5 shows the ¹H NMR result for a crystal generated after two types of DSC A to prepare and confirm an amorphous material.

FIG. 6 shows the result of observing crystalline forms formed by melting-rapid cooling and external stimulation using an optical microscope.

FIG. 7 shows the result of XRPD analysis for a crystalline form formed after melting-rapid cooling and storage.

FIG. 8 shows the result of observing a crystalline form formed after melting-rapid cooling and storage using an optical microscope. (overnight (left), 4 days (right))

FIG. 9 shows the overlaid XRPD diffractogram results of crystalline forms of amorphous Pattern 1, 2, 3, 4 and 6.

FIG. 10 shows the XRPD diffractogram result of the crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101) Pattern 1.

FIG. 11 shows the optical microscope images of the crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101) Pattern 1.

FIG. 12 shows the ¹H NMR result of the crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(5)-2-carbamate (JBPOS0101) Pattern 1.

FIG. 13 shows the UV detection chromatogram result obtained by measuring the UPLC purity of the crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101) Pattern 1.

FIG. 14 is the DSC thermogram of the crystalline form of 1-(2-chlorophenyl)-(5)-1-hydroxypropyl-(5)-2-carbamate (JBPOS0101) Pattern 1.

FIG. 15 is the TGA thermogram of the crystalline form of 1-(2-chlorophenyl)-(5)-1-hydroxypropyl-(5)-2-carbamate (JBPOS0101) Pattern 1 at a temperature of 200° C. or more.

FIG. 16 shows the GVS change in the mass plot of the crystalline form of 1-(2-chlorophenyl)-(5)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101) Pattern 1.

FIG. 17 shows the GVS isotherm plot of the crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(5)-2-carbamate (JBPOS0101) Pattern 1.

FIG. 18 shows the XRPD analysis result for the crystalline form of 1-(2-chlorophenyl)-(5)-1-hydroxypropyl-(S)-2-carbamate before and after GVS.

FIG. 19 shows the result of observing the change in purity before and after GVS through UPLC.

FIG. 20 is the result of forming a competitive slurry, obtained by overlaying XRPD patterns for crystalline forms of Pattern 1 and Pattern 3 and a mixture thereof after DIPE and heptane treatment.

FIG. 21 and FIG. 22 are the results of forming a competitive slurry, obtained by overlaying XRPD patterns for crystalline forms of Pattern 1, Pattern 3, Pattern 6 and Pattern 11 or a mixture thereof after DIPE and heptane treatment.

FIG. 23A shows an X-ray powder diffraction (XRPD) pattern of crystalline form Pattern 2 of Formula 1. FIG. 23B shows a differential scanning calorimetry (DSC) thermogram of crystalline form Pattern 2 of Formula 1. FIG. 23C shows a thermogravimetric analysis (TGA) thermogram of crystalline form Pattern 2 of Formula 1.

FIG. 24A shows an X-ray powder diffraction (XRPD) pattern of crystalline form Pattern 3 of Formula 1. FIG. 24B shows a differential scanning calorimetry (DSC) thermogram of crystalline form Pattern 3 of Formula 1. FIG. 24C shows a thermogravimetric analysis (TGA) thermogram of crystalline form Pattern 3 of Formula 1.

FIG. 25A shows an X-ray powder diffraction (XRPD) pattern of crystalline form Pattern 4 of Formula 1. FIG. 25B shows a differential scanning calorimetry (DSC) thermogram of material following isolation of crystalline form Pattern 4 of Formula 1.

FIG. 26A shows an X-ray powder diffraction (XRPD) pattern of crystalline form Pattern 5 of Formula 1. FIG. 26B shows a differential scanning calorimetry (DSC) thermogram of crystalline form Pattern 5 of Formula 1. FIG. 26C shows a thermogravimetric analysis (TGA) thermogram of crystalline form Pattern 5 of Formula 1.

FIG. 27A shows an X-ray powder diffraction (XRPD) pattern of crystalline form Pattern 6 of Formula 1. FIG. 27B shows a differential scanning calorimetry (DSC) thermogram of crystalline form Pattern 6 of Formula 1. FIG. 27C shows a thermogravimetric analysis (TGA) thermogram of crystalline form Pattern 6 of Formula 1.

FIG. 28A shows an X-ray powder diffraction (XRPD) pattern of crystalline Pattern 7 of Formula 1. FIG. 28B shows a differential scanning calorimetry (DSC) thermogram of freshly isolated crystalline Pattern 7 of Formula 1 (comprising an endothermic peak with an onset at 58.4° C. and an onset at 86.4° C.) and a DSC overlay after standing for 5 days. FIG. 28C shows a thermogravimetric analysis (TGA) thermogram of freshly isolated crystalline Pattern 7 of Formula 1.

FIG. 29A shows an X-ray powder diffraction (XRPD) pattern of crystalline Pattern 8 of Formula 1. FIG. 29B shows a differential scanning calorimetry (DSC) thermogram of freshly isolated crystalline Pattern 8 of Formula 1 (comprising an endothermic peak with an onset at 74° C.) and a DSC overlay after standing for 4 days. FIG. 29C shows a thermogravimetric analysis (TGA) thermogram of freshly isolated crystalline Pattern 8 of Formula 1 (exhibits an about 4.4% (wt %) loss between about 64° C. to about 123° C.) and a TGA overlay after standing for 4 days.

FIG. 30A shows an X-ray powder diffraction (XRPD) pattern of crystalline Pattern 9 of Formula 1. FIG. 30B shows a differential scanning calorimetry (DSC) thermogram of crystalline Form Pattern 9 of Formula 1.

FIG. 31A shows an X-ray powder diffraction (XRPD) pattern of crystalline form Pattern 10 of Formula 1.

FIG. 32A shows an X-ray powder diffraction (XRPD) pattern of crystalline Pattern 11 of Formula 1. FIG. 32B shows a differential scanning calorimetry (DSC) thermogram of crystalline Pattern 11 of Formula 1. FIG. 32C shows a thermogravimetric analysis (TGA) thermogram of crystalline Pattern 11 of Formula 1.

DETAILED DESCRIPTION Definitions

Throughout this disclosure, various patents, patent applications and publications (including non-patent publications) are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a salt, solvate or ester thereof, that, when administered to a patient, is capable of performing the intended result.

The term “substantially similar” as used herein means an analytical spectrum, such as XRPD pattern, DSC thermogram, etc., which resembles the reference spectrum to a great degree in both the peak locations and their intensity.

The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder.

The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and/or the composition. For example, the method for treating depression provides a therapeutic effect when the method reduces at least one symptom of depression in a patient.

Crystalline Forms of Formula 1

The present disclosure provides crystalline forms of the compound of Formula 1:

In embodiments, the present disclosure provides a mixture of one or more crystalline forms of the compound of Formula 1.

In embodiments, the present disclosure provides a substantially pure crystalline form of the compound of Formula 1 as described herein. Crystalline purity may be determined using methods known to those skilled in the art (including, among others, X-ray powder crystallography as described in Shah, B., et al., Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids, J. Pharm. Sci. 2006, 95(8), pages 1641-1665 which is hereby incorporated by reference in its entirety).

In embodiments, the present disclosure relates to an isolated crystalline form of Formula 1 or a pharmaceutically acceptable solvate salt thereof.

In one embodiment, the crystalline form of Formula 1 is crystalline Form Pattern 1, Pattern 2, Pattern 3, Pattern 4, Pattern 5, Pattern 6, Pattern 7, Pattern 8, Pattern 9, Pattern 10, or Pattern 11. In embodiments, the crystalline form of Formula 1 is crystalline Form Pattern 1. In embodiments, the crystalline form of Formula 1 is crystalline Form Pattern 3.

In embodiments, the crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof has a purity of at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% as determined by HPLC analysis. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a purity of at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% as determined by HPLC analysis. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a purity of about 75% to about 99%. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a purity of about 80% to about 99%. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a purity of about 85% to about 99% as determined by HPLC analysis. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a purity of about 90% to about 99% as determined by HPLC analysis. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a purity of about 95% to about 99% as determined by HPLC analysis.

In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a polymorphic purity of at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% with respect to one specific crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a polymorphic purity of at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% with respect to one specific crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a polymorphic purity of about 75% to about 99% with respect to one specific crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a polymorphic purity of about 80% to about 99% with respect to one specific crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has polymorphic a purity of about 85% to about 99% with respect to one specific crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a polymorphic purity of about 90% to about 99% with respect to one specific crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof. In embodiments, the crystalline form of Formula 1, or a pharmaceutically acceptable solvate thereof has a polymorphic purity of about 95% to about 99% with respect to one specific crystalline form of Formula 1 or a pharmaceutically acceptable solvate thereof. Polymorphic purity may be determined using methods known to those skilled in the art (including, among others, X-ray powder crystallography as described in Shah, B., et al, Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids, J. Pharm. Sci. 2006, 95(8), pages 1641-1665 which is hereby incorporated by reference in its entirety).

Crystalline Pattern 1 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 1 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 1. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 1. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 1.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 13.3, 13.4, and 16.2° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises peaks at 11.7 and 14.7±0.2° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises peaks at 11.3 and 17.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises at least one peak selected from 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, or 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises at least two peaks selected from 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, or 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises at least three peaks selected from 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, or 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises at least four peaks selected from 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, or 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises at least five peaks selected from 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, or 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises at least six peaks selected from 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, or 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises at least seven peaks selected from 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, or 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of the compound of Formula 1 further comprises peaks at 6.7, 8.2, 9.8, 13.9, 19.1, 19.4, 24.6, and 27.0° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 13.3±0.2, 13.4±0.2, and 16.2±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 11.3±0.2 and 17.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least one peak selected from 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least two peaks selected from 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least three peaks selected from 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least four peaks selected from 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least five peaks selected from 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least six peaks selected from 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least seven peaks selected from 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, and 27.0±0.2° 20.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 2.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 2.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 2 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to FIG. 10 .

In embodiments, the crystalline form of Formula 1 exhibits an about 5% (wt %) loss between about 39° C. to about 237° C. as determined by thermogravimetric analysis (TGA).

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram comprising an endotherm peak at about 81° C. (onset) with the error of margin of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less.

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram comprising an endotherm peak at about 89° C. (onset) with the error of margin of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less.

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram comprising an endotherm peak at about 229° C. (onset) with the error of margin of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less.

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 14 .

In embodiments, the crystalline form of Formula 1 exhibits a TGA thermogram that is substantially similar to the TGA thermogram of FIG. 15 .

In embodiments, Pattern 1 crystalline form has a melting point of 89° C., and has no considerable mass loss in TGA until decomposed at about 200° C. or more. During a GVS experiment, it was confirmed that there is almost no mass increase within a 0-90% RH range (0.14%), and after the GVS experiment, it was confirmed by XRPD that even when exposed to a high humidity at 40° C./75% RH or RT/97% RH, the Pattern 1 crystalline form has no morphological change.

In embodiments, the pattern I crystalline form of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate) has peaks at diffraction angles (20) of 6.662°, 8.153°, 9.801°, 11.303°, 11.660°, 13.280°, 13.435°, 14.703°, 16.243°, 16.948°, 19.091°, 19.419°, 20.443°, 21.124°, 24.202°, 24.619°, 28.998° and 31.697° in X-ray powder diffraction (XRPD) patterns. Additional peaks may also be shown at one or more diffraction angles (20) of 7.392°, 12.068°, 12.874°, 13.913°, 15.256°, 17.796°, 18.266°, 18.572°, 19.895°, 22.076°, 22.354°, 22.673°, 23.174°, 23.582°, 25.260°, 25.435°, 25.932°, 26.138°, 26.614°, 26.983°, 27.965°, 28.256°, 28.805°, 29.319°, 29.690°, 30.247°, 30.483°, 32.668° and 33.414°.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 1 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 1 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 1 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 1 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 1 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 1 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 1 by weight.

Crystalline Pattern 2 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 2 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 2. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 2. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 2.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 16.3, 19.3, and 20.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 19.8 or 25.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 14.3 and 25.5° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least one peak selected from 6.7, 10.0, 14.0, 22.4, 25.2, 28.1, or 28.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least two peaks selected from 6.7, 10.0, 14.0, 22.4, 25.2, 28.1, or 28.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least three peaks selected from 6.7, 10.0, 14.0, 22.4, 25.2, 28.1, or 28.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least four peaks selected from 6.7, 10.0, 14.0, 22.4, 25.2, 28.1, or 28.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least five peaks selected from 6.7, 10.0, 14.0, 22.4, 25.2, 28.1, or 28.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least one, at least two, at least six peaks selected from 6.7, 10.0, 14.0, 22.4, 25.2, 28.1, or 28.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 6.7, 10.0, 14.0, 22.4, 25.2, 28.1, and 28.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, or at least 17 peaks selected from 8.2, 8.4, 12.9, 13.2, 14.6, 16.8, 22.0, 23.0, 23.7, 26.2, 27.0, 31.7, 34.6, 35.6, 36.0, 37.3, 38.6, or 40.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 8.2, 8.4, 12.9, 13.2, 14.6, 16.8, 22.0, 23.0, 23.7, 26.2, 27.0, 31.7, 34.6, 35.6, 36.0, 37.3, 38.6, and 40.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 16.3±0.2, 19.3±0.2, and 20.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 19.8±0.2 or 25.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 14.3±0.2 and 25.5±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least one peak selected from 6.7±0.2, 10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, or 28.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least two peaks selected from 6.7±0.2, 10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, or 28.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least three peaks selected from 6.7±0.2, 10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, or 28.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least four peaks selected from 6.7±0.2, 10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, or 28.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least five peaks selected from 6.7±0.2, 10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, or 28.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least six peaks selected from 6.7±0.2, 10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, or 28.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 6.7±0.2, 10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, and 28.6±0.2° 20. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, or at least 17 peaks selected from 8.2±0.2, 8.4±0.2, 12.9±0.2, 13.2±0.2, 14.6±0.2, 16.8±0.2, 22.0±0.2, 23.0±0.2, 23.7±0.2, 26.2±0.2, 27.0±0.2, 31.7±0.2, 34.6±0.2, 35.6±0.2, 36.0±0.2, 37.3±0.2, 38.6±0.2, or 40.1±0.2° 20. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 8.2±0.2, 8.4±0.2, 12.9±0.2, 13.2±0.2, 14.6±0.2, 16.8±0.2, 22.0±0.2, 23.0±0.2, 23.7±0.2, 26.2±0.2, 27.0±0.2, 31.7±0.2, 34.6±0.2, 35.6±0.2, 36.0±0.2, 37.3±0.2, 38.6±0.2, and 40.1±0.2° 20.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 7.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 7.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 7 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to FIG. 23A.

In embodiments, the crystalline form of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at about 49° C.

In embodiments, the crystalline form of Formula 1 exhibits an about 9% (wt %) loss between about 58° C. to about 191° C. as determined by thermogravimetric analysis (TGA).

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 23B.

In embodiments, the crystalline form of Formula 1 exhibits a TGA thermogram that is substantially similar to the TGA thermogram of FIG. 23C.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 2 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 2 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 2 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 2 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 2 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, about 95.0% to 100% Pattern 2 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 2 by weight.

Crystalline Pattern 3 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 3 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 3. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 3. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 3.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.9, 15.8, and 17.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 8.9 and 13.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 17.0 and 17.5° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least one peak selected from 15.2, 19.8, 23.2, 24.0, 28.2, 30.4, or 30.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least two peaks selected from 15.2, 19.8, 23.2, 24.0, 28.2, 30.4, or 30.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least three peaks selected from 15.2, 19.8, 23.2, 24.0, 28.2, 30.4, or 30.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least four peaks selected from 15.2, 19.8, 23.2, 24.0, 28.2, 30.4, or 30.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least five peaks selected from 15.2, 19.8, 23.2, 24.0, 28.2, 30.4, or 30.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least six peaks selected from 15.2, 19.8, 23.2, 24.0, 28.2, 30.4, or 30.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 15.2, 19.8, 23.2, 24.0, 28.2, 30.4, and 30.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 10.9±0.2, 15.8±0.2, and 17.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 8.9±0.2 and 13.4±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 17.0±0.2 and 17.5±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern further comprising at least one peak selected from 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or 30.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern further comprising at least two peaks at 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or 30.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern further comprising at least three peaks at 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or 30.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern further comprising at least four peaks at 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or 30.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern further comprising at least five peaks at 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or 30.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern further comprising at least six peaks at 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or 30.8±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern further comprising peaks at 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, and 30.8±0.2° 20.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 8.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 8.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 8 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to the XRPD pattern of FIG. 24A.

In embodiments, the crystalline form of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at about 82° C.

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 24B.

In embodiments, the crystalline form of Formula 1 exhibits a TGA thermogram that is substantially similar to the TGA thermogram of FIG. 24C.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 3 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 3 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 3 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 3 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 3 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 3 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 3 by weight.

Crystalline Pattern 4 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 4 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 4. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 4. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 4.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 8.6, 17.3, and 17.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form Formula 1 further comprises peaks at 13.7 or 28.5° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 13.4 or 20.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least one peak at 6.9, 17.0, 19.6, 25.4, 26.1, 26.8, or 32.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least two peaks selected from 6.9, 17.0, 19.6, 25.4, 26.1, 26.8, or 32.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least three peaks selected from 6.9, 17.0, 19.6, 25.4, 26.1, 26.8, or 32.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least four peaks selected from 6.9, 17.0, 19.6, 25.4, 26.1, 26.8, or 32.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least five peaks selected from 6.9, 17.0, 19.6, 25.4, 26.1, 26.8, or 32.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises at least six peaks selected from 6.9, 17.0, 19.6, 25.4, 26.1, 26.8, or 32.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the XRPD of the crystalline form of Formula 1 further comprises peaks at 6.9, 17.0, 19.6, 25.4, 26.1, 26.8, and 32.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 8.6±0.2, 17.3±0.2, and 17.4±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 13.7±0.2 or 28.5±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 13.4±0.2 or 20.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least one peak at 6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, or 32.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least two peaks selected from 6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, or 32.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least three peaks selected from 6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, or 32.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least four peaks selected from 6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, or 32.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least five peaks selected from 6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, or 32.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least six peaks selected from 6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, or 32.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, and 32.1±0.2° 20.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 9.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 9.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 9 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to FIG. 25A.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 4 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 4 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 4 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 4 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 4 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 4 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 4 by weight.

Crystalline Pattern 5 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 5 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 5 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 5. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 5. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 5.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 13.3, 15.8 and 17.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 10.9 and 19.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 6.6, 8.9, 13.2, 16.2, 17.0, 17.5, or 19.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks selected from 6.6, 8.9, 13.2, 16.2, 17.0, 17.5, or 19.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least three peaks selected from 6.6, 8.9, 13.2, 16.2, 17.0, 17.5, or 19.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least four peaks selected from 6.6, 8.9, 13.2, 16.2, 17.0, 17.5, or 19.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least five peaks selected from 6.6, 8.9, 13.2, 16.2, 17.0, 17.5, or 19.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least six peaks selected from 6.6, 8.9, 13.2, 16.2, 17.0, 17.5, or 19.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 6.6, 8.9, 13.2, 16.2, 17.0, 17.5, and 19.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 13.3±0.2, 15.8±0.2 and 17.8±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 10.9±0.2 and 19.8±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 6.6±0.2, 8.9±0.2, 13.2±0.2, 16.2±0.2, 17.0±0.2, 17.5±0.2, or 19.4±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks selected from 6.6±0.2, 8.9±0.2, 13.2±0.2, 16.2±0.2, 17.0±0.2, 17.5±0.2, or 19.4±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least three peaks selected from 6.6±0.2, 8.9±0.2, 13.2±0.2, 16.2±0.2, 17.0±0.2, 17.5±0.2, or 19.4±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least four peaks selected from 6.6±0.2, 8.9±0.2, 13.2±0.2, 16.2±0.2, 17.0±0.2, 17.5±0.2, or 19.4±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least five peaks selected from 6.6±0.2, 8.9±0.2, 13.2±0.2, 16.2±0.2, 17.0±0.2, 17.5±0.2, or 19.4±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least six peaks selected from 6.6±0.2, 8.9±0.2, 13.2±0.2, 16.2±0.2, 17.0±0.2, 17.5±0.2, or 19.4±0.2° 20. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 6.6±0.2, 8.9±0.2, 13.2±0.2, 16.2±0.2, 17.0±0.2, 17.5±0.2, and 19.4±0.2° 20.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks Table 10.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 10.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 10 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to FIG. 26A.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 5 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 5 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 5 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 5 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 5 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 5 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 5 by weight.

Crystalline Pattern 6 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 6 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 6. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 6. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 6.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 6.6, 14.1, and 16.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 10.0 and 19.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 8.3, and 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 16.4, 16.6, 20.5, and 25.6° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 6.6 and 14.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0 and 19.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least one peak at 8.3, 19.3, 22.5, 25.6, 25.9, or 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least two peaks selected from 8.3, 19.3, 22.5, 25.6, 25.9, or 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least three peaks selected from 8.3, 19.3, 22.5, 25.6, 25.9, or 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least four peaks selected from 8.3, 19.3, 22.5, 25.6, 25.9, or 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least five peaks selected from 8.3, 19.3, 22.5, 25.6, 25.9, or 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 8.3, 19.3, 22.5, 25.6, 25.9, and 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 6.6±0.2, 14.1±0.2, and 16.4±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0±0.2, and 19.9±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 8.3±0.2, and 28.4±0.2° 20.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 16.4±0.2, 16.6±0.2, 20.5±0.2, and 25.6±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 6.6±0.2 and 14.1±0.2° 20. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0±0.2 and 19.9±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least one peak at 8.3±0.2, 19.3±0.2, 22.5±0.2, 25.6±0.2, 25.9±0.2, or 28.4±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least two peaks selected from 8.3±0.2, 19.3±0.2, 22.5±0.2, 25.6±0.2, 25.9±0.2, or 28.4±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least three peaks selected from 8.3±0.2, 19.3±0.2, 22.5±0.2, 25.6±0.2, 25.9±0.2, or 28.4±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least four peaks selected from 8.3±0.2, 19.3±0.2, 22.5±0.2, 25.6±0.2, 25.9±0.2, or 28.4±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least five peaks selected from 8.3±0.2, 19.3±0.2, 22.5±0.2, 25.6±0.2, 25.9±0.2, or 28.4±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks selected from 8.3±0.2, 19.3±0.2, 22.5±0.2, 25.6±0.2, 25.9±0.2, and 28.4±0.2° 2θ.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 11.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 11.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 11 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to FIG. 27A.

In embodiments, the crystalline form of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at about 72° C.

In embodiments, the crystalline form of Formula 1 exhibits an about 4.8% (wt %) loss between about 70° C. to about 161° C. as determined by thermogravimetric analysis (TGA).

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 27B.

In embodiments, the crystalline form of Formula 1 exhibits a TGA thermogram that is substantially similar to the TGA thermogram of FIG. 27C.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 6 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 6 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 6 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 6 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 6 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 6 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 6 by weight.

Crystalline Pattern 7 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 7 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 7. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 7. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 7.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0, 15.0, and 16.3° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0, 15.0, 16.3, and 21.3° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 25.8 and 31.1 with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 25.1, 28.2, or 30.2° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks selected from 25.1, 28.2, or 30.2° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 25.1, 28.2, and 30.2° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0±0.2, 15.0±0.2, and 16.3±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0±0.2, 15.0±0.2, 16.3±0.2, and 21.3±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 25.8±0.2 and 31.1±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 25.1±0.2, 28.2±0.2, or 30.2±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks selected from 25.1±0.2, 28.2±0.2, or 30.2±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 25.1±0.2, 28.2±0.2, and 30.2±0.2° 2θ.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 12.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 12.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 12 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to FIG. 28A.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 7 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 7 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 7 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 7 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 7 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 7 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 7 by weight.

Crystalline Pattern 8 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 8 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 8. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 8. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 8.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0, 15.0, and 16.2° 2θ, with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 20.0 and 31.1° 2θ, with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 21.3, 25.1. 28.1, 30.2, or 31.1, with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks selected from 21.3, 25.1. 28.1, 30.2, or 31.1, with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least three peaks selected from 21.3, 25.1. 28.1, 30.2, or 31.1, with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least four peaks selected from 21.3, 25.1. 28.1, 30.2, or 31.1 with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks selected at 21.3, 25.1. 28.1, 30.2, and 31.1, with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0±0.2, 15.0±0.2, and 16.2±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 20.0±0.2 and 31.1±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 21.3±0.2, 25.1±0.2. 28.1±0.2, 30.2±0.2, or 31.1±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks selected from 21.3±0.2, 25.1±0.2. 28.1±0.2, 30.2±0.2, or 31.1±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least three peaks selected from 21.3±0.2, 25.1±0.2. 28.1±0.2, 30.2±0.2, or 31.1±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least four peaks selected from 21.3±0.2, 25.1±0.2. 28.1±0.2, 30.2±0.2, or 31.1±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 21.3±0.2, 25.1±0.2. 28.1±0.2, 30.2±0.2, or 31.1±0.2° 2θ.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 13.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 13.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 13 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to FIG. 29A.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 8 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 8 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 8 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 8 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 8 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 8 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 8 by weight.

Crystalline Pattern 9 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 9 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 9. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 9. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 9.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0, 16.4, and 25.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 15.0 and 28.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at least one peak at 8.4, 12.0, 14.2, 20.0, 21.1, 25.1, or 30.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at least two peaks selected from 8.4, 12.0, 14.2, 20.0, 21.1, 25.1, or 30.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at least three peaks selected from 8.4, 12.0, 14.2, 20.0, 21.1, 25.1, or 30.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at least four peaks selected from 8.4, 12.0, 14.2, 20.0, 21.1, 25.1, or 30.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at least five peaks selected from 8.4, 12.0, 14.2, 20.0, 21.1, 25.1, or 30.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at least six peaks selected from 8.4, 12.0, 14.2, 20.0, 21.1, 25.1, or 30.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 8.4, 12.0, 14.2, 20.0, 21.1, 25.1, and 30.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0±0.2, 16.4±0.2, and 25.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 15.0±0.2 and 28.4±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least one peak at 8.4±0.2, 12.0±0.2, 14.2±0.2, 20.0±0.2, 21.1±0.2, 25.1±0.2, or 30.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least two peaks selected from 8.4±0.2, 12.0±0.2, 14.2±0.2, 20.0±0.2, 21.1±0.2, 25.1±0.2, or 30.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least three peaks selected from 8.4±0.2, 12.0±0.2, 14.2±0.2, 20.0±0.2, 21.1±0.2, 25.1±0.2, or 30.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least four peaks selected from 8.4±0.2, 12.0±0.2, 14.2±0.2, 20.0±0.2, 21.1±0.2, 25.1±0.2, or 30.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least five peaks selected from 8.4±0.2, 12.0±0.2, 14.2±0.2, 20.0±0.2, 21.1±0.2, 25.1±0.2, or 30.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least six peaks selected from 8.4±0.2, 12.0±0.2, 14.2±0.2, 20.0±0.2, 21.1±0.2, 25.1±0.2, or 30.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 8.4±0.2, 12.0±0.2, 14.2±0.2, 20.0±0.2, 21.1±0.2, 25.1±0.2, and 30.9±0.2° 2θ.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 14.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 14.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 14 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to the XRPD pattern of FIG. 30A.

In embodiments, the crystalline form of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram comprising endothermic peaks with an onset at about 63° C., about 81° C. and about 88° C.

In embodiments, the crystalline form of Formula 1 exhibits a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 30B.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 9 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 9 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 9 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 9 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 9 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 9 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 9 by weight.

Crystalline Pattern 10 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 10 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 1 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 10. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 10. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 10.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 14.7, 16.6, 22.1, 24.7, and 26.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 11.9 and 13.4° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least three peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least four peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least five peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least six peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least seven peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least eight peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least nine peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, or 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 12.6, 15.8, 18.5, 21.5, 22.6, 22.8, 24.5, 25.1, and 29.4, and 38.8° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 14.7±0.2, 16.6±0.2, 22.1±0.2, 24.7±0.2, and 26.9±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 11.9±0.2 and 13.4±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least one peak at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least two peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least three peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least four peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least five peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least six peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least seven peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least eight peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising at least nine peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2, 24.5±0.2, 25.1±0.2, and 29.4±0.2, and 38.8±0.2° 2θ.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 15.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 15.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 15 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to the XRPD pattern of FIG. 31A.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 10 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 10 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 10 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 10 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 10 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 10 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 10 by weight.

Crystalline Pattern 11 of Formula 1

In embodiments, the present disclosure provides a crystalline Pattern 11 of the compound of Formula 1.

In embodiments, the crystalline form of Formula 11 comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Pattern 11. In embodiments, the crystalline form of Formula 1 comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Pattern 11. In some embodiments, the crystalline form of Formula 1 comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Pattern 11.

In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0, 14.3, 16.3, 19.9 and 20.1° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 27.9 and 28.2° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least one peak at 6.6, 8.2, 8.4, 14.3, 21.4, or 25.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least two peaks at 6.6, 8.2, 8.4, 14.3, 21.4, or 25.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least three peaks at 6.6, 8.2, 8.4, 14.3, 21.4, or 25.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least four peaks at 6.6, 8.2, 8.4, 14.3, 21.4, or 25.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising at least five peaks at 6.6, 8.2, 8.4, 14.3, 21.4, or 25.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05. In embodiments, the crystalline form of Formula 1 exhibits an XRPD pattern further comprising peaks at 6.6, 8.2, 8.4, 14.3, 21.4, and 25.9° 2θ with the margin of error of about ±0.2; about ±0.1; or about ±0.05.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 10.0±0.2, 14.3±0.2, 16.3±0.2, 19.9±0.2 and 20.1±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 27.9±0.2 and 28.2±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least one peak at 6.6±0.2, 8.2±0.2, 8.4±0.2, 14.3±0.2, 21.4±0.2, or 25.9±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least two peaks at 6.6±0.2, 8.2±0.2, 8.4±0.2, 14.3±0.2, 21.4±0.2, or 25.9±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least three peaks at 6.6±0.2, 8.2±0.2, 8.4±0.2, 14.3±0.2, 21.4±0.2, or 25.9±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least four peaks at 6.6±0.2, 8.2±0.2, 8.4±0.2, 14.3±0.2, 21.4±0.2, or 25.9±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising at least five peaks at 6.6±0.2, 8.2±0.2, 8.4±0.2, 14.3±0.2, 21.4±0.2, or 25.9±0.2° 2θ. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising peaks at 6.6±0.2, 8.2±0.2, 8.4±0.2, 14.3±0.2, 21.4±0.2, and 25.9±0.2° 2θ.

In some embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks of Table 16.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD comprising peaks shown in Table 16.

In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 5%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 10%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 20%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 25%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 30%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 35%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 40%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 45%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 50%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 60%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 70%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 80%. In embodiments, the crystalline form of the compound of Formula 1 exhibits an XRPD pattern comprising one or more peaks from Table 16 having intensity of at least 90%.

In one specific embodiment, the crystalline form of Formula 1 exhibits an XRPD pattern that is substantially similar to the XRPD pattern of FIG. 32A.

In embodiments, the crystalline form of Formula 1 exhibits a differential scanning calorimetry (DSC) thermogram comprising endothermic peaks with an onset at about 70° C. and about 89° C.

In embodiments, the crystalline form of Formula 1 exhibits an about 3% (wt %) loss between about 73° C. to about 112° C. as determined by thermogravimetric analysis (TGA).

In embodiments, the crystalline form of Formula 1 exhibits:

-   -   a) a DSC thermogram that is substantially similar to the DSC         thermogram of FIG. 32B; or     -   b) a TGA thermogram that is substantially similar to the TGA         thermogram of FIG. 32C.

In some embodiments, the crystalline form of Formula 1 is at least about 90% Pattern 11 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 11 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 95% Pattern 11 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 99% Pattern 11 by weight. In some embodiments, the crystalline form of Formula 1 is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Pattern 11 by weight.

In some embodiments, the crystalline form of Formula 1 is about 70% to about 100%, about 85.0% to 100%, or about 95.0% to 100% Pattern 11 by weight. In some embodiments, the crystalline form of Formula 1 is about 98.0% to 100% Pattern 11 by weight.

In embodiments of the present invention, the crystalline form of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate) was dissolved in one or more solvents selected from 1,4-dioxane, t-butanol, dichloromethane and/or water, or maintained for a predetermined time after dissolution, thereby obtaining an amorphous product. Afterward, the resulting product was crystallized by polymorphic screening using a solvent, thereby obtaining polymorphic patterns.

As a solvent used in the polymorphic screening, a solvent selected from the group consisting of diethyl ether, pentane, ethyl formate, tert-butylmethyl ether, acetone, methyl acetate, chloroform, methanol, tetrahydrofuran, diisopropyl ether, ethyl acetate, ethanol, methyl ethyl ketone, acetonitrile, 2-propanol, tert-butanol, 1,2-dimethoxyethane, isopropyl acetate, 1-propanol, 2-butanol, heptane, water, formic acid, 1,4-dioxane, propyl acetate, 2-pentanone, 2-methyl-1-propanol, toluene, isobutyl acetate, methyl isobutyl ketone, 1-butanol, acetic acid, 2-methoxyethanol, butyl acetate, methyl butyl ketone, 3-methyl-1-butanol, 2-ethoxyethanol, 1-pentanol, cumene, anisole, benzonitrile, dimethyl sulfoxide and benzyl alcohol, and a mixed solvent thereof was used, and more preferably, a solvent for screening the Pattern 1 crystalline form, such as a solvent selected from the group consisting of acetone, chloroform, MeOH, tetrahydrofuran, diisopropyl ether, ethanol (EtOH), methyl ethyl ketone, acetonitrile, 2-propanol, tert-butanol), 1,2-dimethoxyethane (DME), 1-propanol, 2-butanol, water, 1,4-dioxane, 2-methyl-1-propanol, 2-methoxyethanol, butyl acetate, methyl butyl ketone, 3-methyl-1-butanol, 1-pentanol, cumene and anisole, and a mixed solvent thereof was used.

In another aspect of the present invention, the present invention provides a pharmaceutical composition including the crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101).

The pharmaceutical composition may be used as a pharmaceutical composition for a similar use to that of phenyl carbamate or a derivative thereof, and more specifically, a composition for treating or preventing one or more diseases selected from the group consisting of muscle relaxation, spasticity, spasms, central nervous system disorders, Lou Gehrig's disease, multiple sclerosis, pain, stroke, epilepsy, epilepsy-related syndrome, pediatric epilepsy, pediatric epilepsy-related syndrome, memory loss-related disease, nerve gas-induced disease, psychiatric disorder, movement disorder and neurological injury disease.

More specifically, wherein the memory loss-related disease comprising senile dementia or Alzheimer's disease; wherein the nerve gas-induced disease comprising spasm, gastrointestinal distress, emesis, rhinorrhea, miosis, bronchoconstriction, fasciculation, floppy paralysis, apnea, diaphoresis and diarrhea; wherein the psychiatric disorder comprising depressive, bipolar disorders, anxiety disorder and seizures; wherein the movement disorder comprising ataxia, corticobasal ganglionic degeneration (CBGD), dyskinesia, dystonia, tremors, essential tremor, Parkinsonian tremor, hereditary spastic paraplegia, multiple system atrophy, myoclonus, Parkinson's disease, progressive supranuclear palsy, restless legs syndrome, Rett syndrome, spasticity, Sydenham's chorea, other choreas, athetosis, ballism, stereotypy, tardive dyskinesia/dystonia, tics, Tourette's syndrome, olivopontocerebellar atrophy (OPCA), hemibalismus, hemi-facial spasm, Wilson's disease, stiff man syndrome, akinetic mutism, psychomotor retardation, painful legs moving toes syndrome, a gait disorder, and a drug-induced movement disorder; wherein the neurological injury disease comprising neurodegenerative disease, autism spectrum disease and prion diseases; wherein the neurodegenerative disease is selected from the group consisting of Huntington's disease, Pick's disease, diffuse Lewy body disease, drug intoxication or withdrawal, Steel-Richardson syndrome, Shy-Drager syndrome, cortical basal degeneration, subacute sclerosing panencephalitis, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease, spinocerebellar ataxia, olivopontocerebellar degenerations, macular degeneration, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy, systemic lupus erythematosus, primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leuko-encephalopathy and familial dysautonomia; wherein the autism spectrum disease is selected from the group consisting of autism, Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS); and wherein the prion diseases is selected from the group consisting of Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, Kuru disease and fatal familial insomnia.

In addition, the pharmaceutical composition of the present invention may be formulated in various oral dosage forms or parenteral dosage forms. For example, the pharmaceutical composition may be prepared in any formulation for oral administration such as tablets, pills, soft/hard capsules, liquids, suspensions, emulsions, syrups, granules, and elixirs. The oral formulation may include a pharmaceutically available carrier such as a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, or a glidant such as silica, talc, stearic acid and a magnesium or calcium salt thereof and/or polyethylene glycol, in addition to the active ingredient, according to a conventional composition of each formulation.

In addition, when the oral formulation is a tablet, it may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, it may also include a disintegrant such as starch, agar, alginic acid or a sodium salt thereof or a boiling mixture, and/or an absorbent, a colorant, a flavoring agent or a sweetening agent.

In addition, the pharmaceutical composition may be formulated in a parenteral dosage form, and administered by a parenteral administration method such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. Here, to prepare the parenteral formulations, the pharmaceutical composition may be prepared in a solution or suspension by mixing an active ingredient with a stabilizing agent or buffer in water, and the solution or suspension may be dispensed into a unit dosage form of an ampoule or vial.

In addition, the pharmaceutical composition may be sterilized or further include additives such as a preservative, a stabilizing agent, a wetting agent or emulsifier, a salt for osmotic control and/or a buffer, and may further include other therapeutically useful materials. The pharmaceutical composition may be prepared by a conventional method such as mixing, granulation or coating.

In addition, the active ingredient may be administered daily at a therapeutically effective amount of 0.01 to 750 mg/kg (body weight), and preferably 0.1 to 500 mg/kg (body weight) for mammals including humans. Such a pharmaceutical composition may be administered once or in a two or more divided portions a day via oral or parenteral routes.

EXAMPLES

Hereinafter, the present invention will be described in detail with reference to examples to help in understanding the present invention. However, examples according to the present invention may be modified into a variety of different forms, and it should not be construed that the scope of the present invention is limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

Experimental Methods X-Ray Powder Diffraction (XRPD)

XRPD patterns were detected by CuKα irradiation (30 kV, 10 mA) using a Bruker AXS D2 diffractometer. The analysis was performed using θ-θ geometry and a LynxEye detector at 5 to 42° 2θ with a step size of 0.024° 2θ at 0.1 sec/step.

The software used for data collection was DIFFRAC. SUITE, and the data was analyzed and presented using Diffrac Plus EVA v 16.0.0.0.

Samples were run at ambient conditions and prepared as flat specimens using powder received without grinding. About 1 to 2 mg of the sample was lightly pressed on a silicon wafer to obtain a flat surface.

Single Crystal X-Ray Diffraction (SCXRD)

SCXRD analysis was performed by Rbar3 Ltd.

Nuclear Magnetic Resonance Spectroscopy (NMR)

A solution phase ¹H NMR spectrum was obtained using a 5-mm PABBO probe-installed Bruker AVIIIHD NMR spectrometer operated at 400.1326 MHz. Samples were prepared with d6-DMSO unless otherwise specified and referenced using TMS internal standards.

Differential Scanning calorimetry (DSC)

DSC data was collected on a Mettler DSC 3+equipped with a 34 position auto-sampler. The instrument was calibrated for energy and temperature using certified indium. Generally, 0.5 to 3 mg of each sample was heated from 30 to 300° C. at 10° C./min in a pinhole aluminum pan. A nitrogen purge was maintained over the sample at 50 mL/min. STARe v15.00 was used for instrument control and data processing.

Thermogravimetric Analysis (TGA)

TGA data were collected on a Mettler TGA 2 equipped with a 34 position auto-sampler. The instrument was calibrated for energy and temperature using certified isotherm and nickel. Generally, 0.5 to 30 mg of each sample was heated at from 30 to 400° C. at 10° C./min in a pinhole aluminum pan. A nitrogen purge was maintained over the sample at 50 mL/min. STARe v15.00 was used for instrument control and data processing.

Polarized Light Microscopy (PLM)

A digital video camera-equipped Nikon DLM polarization microscope was used to capture sample images. A small amount of sample was placed on a glass slide, mounted in an immersion oil, and covered with a glass slip for individually isolating particles as much as possible. The sample was observed with appropriate magnification and partial polarization, coupled to a λ additive color filter.

Particle Size Distribution (PSD) by Laser Diffraction

PSD was measured using a Sympatec HELOS/BF particle sizer equipped with a RODOS/ASPIROS dry dispenser operating at 2.5 Bar with a sled speed of 25 mm/s. R1 0.1/0.18 μm-35 μm and R3 0.5/0.9 μm-175 μm lenses were combined and used for observation. Unless specified otherwise, a trigger condition of 1 ms 0.2% Ch27 was used.

Gravimetric Vapor Sorption (GVS)

Sorption isotherms were obtained using an SMS DVS intrinsic water absorption analyzer controlled by SMS Analysis Suite software. A sample temperature was maintained at 25° C. throughout. Humidity was controlled by a mixed stream of dry and wet nitrogen with a total flow rate of 200 mL/min. The relative humidity was measured with a calibrated Rotronic probe (dynamic range: 1.0-100% RH) located near the sample. The weight change (mass relaxation) of the sample as a function of % RH was continuously monitored using a microbalance (accuracy±0.005 mg). 5 to 20 mg of the sample was stored in a prepared stainless steel mesh basket under atmospheric conditions.

Measurement of Thermodynamic Solubility by UPLC

A thermodynamic solubility in water was determined by providing a suitable concentration of compound prepared by suspending a sufficient compound in water or buffer according to estimated solubilities of the medium and the compound. Quantification was done by UPLC with reference to a standard calibration curve. A solubility was calculated with QuanLynx using a peak area determined by the integration of a peak found at the same retention time as the main peak in the standard injection.

HPLC (High Performance Liquid Chromatography) Method for Chemical Purity HPLC Method Parameters for Chemical Purity Determinations

Column: Waters Xbridge Phenyl, 4.6 × 150 mm, 3.5 μm Oven Temperature (° C.): 40° C. Sample Temperature (° C.): 5° C. Injection (μL): 10 Run Time (min): 25 Detection: Wavelength, UV Diode array 212 nm Bandwidth (nm): Mobile Phase A: 0.1% phosphoric acid in purified water Mobile Phase B: 0.1% phosphoric acid in acetonitrile Diluent Solution: 0.01% trifluoroacetic acid in acetonitrile Needle Wash Solvent: 50% acetonitrile in purified water Flow Rate (mL/min): 1.0 Timetable Time (min) % Phase A % Phase B 0.0 95 5 17.0 30 70 17.1 95 5 25.0 95 5

Analytical Preparation

-   -   a. Reagents: Acetonitrile (HPLC grade or equivalent), Water         (HPLC grade or equivalent), Trifluoroacetic acid (HPLC grade or         equivalent), Phosphoric acid, reference standard of JBPOS0101     -   b. Apparatus: Volumetric flask, Micro Pipette, Balance

Analytical Procedure

-   -   a. Preparation of mobile phase:         -   Mobile Phase A: Take 1 mL of phosphoric acid into the 1 L             volumetric flask and marked as water         -   Mobile Phase B: Take 1 mL of phosphoric acid into the 1 L             volumetric flask and marked as acetonitrile     -   b. Preparation of diluent solution: Take 0.1 mL of         trifluoroacetic acid into the 1 L volumetric flask and marked as         acetonitrile     -   c. Preparation of standard solution: Precisely weigh 12.5 mg of         reference standard of JBPOS0101 and transfer it into a 100 mL         volumetric flask. Add diluent and dilute to volume.     -   d. Preparation of sample solution: Precisely weigh 12.5 mg of         sample and transfer it into a 100 mL volumetric flask. Add         diluent and dilute to volume.

Example 1. Preparation of amorphous 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101/S-P-17001) was obtained from Bio-Pharm Solutions Co. Ltd. A method of preparing a phenyl carbamate compound, JBPOS0101, is described in Korean Patent No. 10-2014-0113918 A.

The CRL batch reference number for a crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate is ED01748-006-001-00, and has characteristics of Table 1 below.

TABLE 1 Bio-Pharm Solutions Co. Ltd. Batch reference JBPOS0101/S-P-17001 CRL batch reference ED01748-006-001-00 Appearance White crystalline solid Molecular formula C₁₀H₁₂ClNO₃ Molecular weight 229.66 ¹H NMR Consistent with structure UPLC Purity³ 98.6% XRPD Crystalline by XRPD, assigned as Pattern 1 DSC DSC shows a very small endothermic event of onset 81° C. (peak 82° C.), followed by a sharp endothermic event of onset 89° C. (peak 90° C.) consistent with a melt. Broad peak of onset 229° C.-decomposition TGA TGA shows 95% of mass remaining at 237° C. with no significant mass loss until above ca. 200° C. 100% of mass was lost by 305° C. PSD D10 D50 D90 0.95 μm 4.51 μm 41.92 μm Log D (shake flask at pH 5), Log P Log D_(pH5) = 1.32, Log P = 1.32 GVS Shows a 0.14% mass increase over the second sorption cycle (0-90% RH) XRPD post GVS (ED01748-006-002-00) Shows no change in form by XRPD post GVS XRPD post storage at 40° C./75% RH for Shows no change in form by XRPD post storage 7 days (ED01748-006-003-00) at 40° C./75% RH for 7 days UPLC purity post storage at 40° C./75% RH 97.4% for 7days (ED01748-006-003-00) ¹H NMR post storage at 40° C./75% RH for Consistent with structure 7 days (ED01748-006-003-00) XRPD post storage at RT/97% RH for 7 days Shows no change in form by XRPD post storage (ED01748-006-004-00) at RT/97% RH for 7 days UPLC purity post storage at RT/97% RH for 97.7% 7 days (ED01748-006-004-00) ¹H NMR purity post storage at RT/97% RH Consistent with structure for 7 days (ED01748-006-004-00)

For screening of various polymorphisms of the material, first, the material was amorphized, and the resulting amorphous material was used as a material for polymorphic screening with various solvents.

<1-1> Preparation of Amorphous Form by 1,4-dioxane

A portion of ED01748-006-001-00 (15 mg) was dissolved in 1,4-dioxane (0.1 mL). A white solid ED01748-009-001-00 was prepared by flash freezing in a dry ice/acetone bath and freeze-drying the prepared solution, and as a result of XRPD analysis, a crystalline form (Pattern 2) with a different pattern was identified (FIG. 1 ). In addition, as a result of reanalysis of the ED01748-006-001-00 sample after being left overnight on the XRPD disc under laboratory conditions, a crystalline form with a novel pattern (ED01748-009-005-00, Pattern 3) was identified (FIG. 2 ).

<1-2> Preparation of Amorphous Form by 1,4-dioxane/water

ED01748-006-001-00 (10 mg) was dissolved in 1,4-dioxane (0.2 mL) and water (0.1 mL).

A white solid ED01748-013-001-00 was prepared by flash freezing in a dry ice/acetone bath and freeze-drying the prepared solution. As a result of XRPD analysis of the solution, a crystalline form with the same pattern as obtained by freeze-drying in 1,4-dioxane (Pattern 2) was identified.

<1-3> Preparation of Amorphous Form by t-Butanol

A portion of ED01748-006-001-00 (10 mg) was dissolved in t-butanol (0.25 mL). ED01748-009-006-00 with high viscosity was obtained by flash freezing in a dry ice/acetone bath and freeze-drying the prepared solution. According to the XRPD analysis of the material, the crystallinity of Pattern 1 was identified (FIG. 3 ).

<1-4> Preparation of Amorphous Form by t-Butanol/Water

A portion of ED01748-006-001-00 (10 mg) was dissolved in t-butanol (0.2 mL) and water (0.1 mL). A viscous material mixture (ED01748-013-002-00) was provided by flash freezing in a dry ice/acetone bath and freeze-drying the prepared solution. It was confirmed that the result of XRPD analysis corresponds to Pattern 1 (FIG. 3 ).

<1-5> Preparation of Amorphous Form by Evaporation of DCM Solution

A portion of ED01748-006-001-00 (20 mg) was dissolved in dichloromethane (DCM)(2 mL), and then the solution was rapidly evaporated under vacuum, thereby obtaining a colorless viscous material. After standing overnight, the total sample was solidified (ED01748-009-004-00), and it was confirmed that the XRPD analysis result corresponds to Pattern 1 (FIG. 4 ).

<1-6> DSC Experiment for Preparing Amorphous Material

To prepare and confirm an amorphous material, two types of DSC experiments (AB) were performed on ED01748-006-001-00.

DSC A experiment

A portion of ED01748-006-001-00 was heated in a differential scanning calorimeter at 10° C./min to 110° C., and then cooled to 30° C. at 50° C./min. The contents of a DSC pan were analyzed by ¹H NMR. As a result, after melting and cooling, no degradation or migration of the sample was observed (FIG. 5 ).

DSC B Experiment

A portion of ED01748-006-001-00 was heated in a differential scanning calorimeter at 10° C./min to 110° C., and then cooled to −30° C. at 10° C./min, followed by heating again to 300° C.

Finally, as the sample was heated, a glass transition temperature (Tg) was observed at 14.6° C. (median: 15.3° C.), and other thermal changes were not observed until the sample was decomposed at about 190° C. or more.

In both DSC experiments A and B, the sample was dissolved and then cooled, thereby generating an amorphous material, and there was no evidence of decomposition by NMR. Experiment B showed a low glass transition temperature (Tg onset: 14.6° C.) of the material, indicating that the stability of the amorphous material may be an issue.

<1-7> Preparation of Amorphous Form by Melting and Rapid Cooling

Each (about 10 mg) of two ED01748-006-001-00 samples was put into a vial, and then into a drying pistol which had been preheated to 110° C. for 10 minutes under ambient pressure. The molten sample was removed, followed by rapid cooling with dry ice. As a result of observation with an optical microscope, glass droplets were observed as shown in FIG. 6 . The glass material from the first sample was rapidly crystallized by impacting a part that characterized it. As a result of XRPD analysis, the glass material was identified as Pattern 1 (FIG. 7 ). The material was not significantly decomposed as confirmed by ¹H NMR or UPLC, and the sample had a UPLC purity of 98.7%.

The second sample of the cooled material was stored in a closed vial overnight and observed using an optical microscope. A very small amount of crystalline material was observed (FIG. 8 , left), and after standing for 4 days, it was confirmed that the material was completely crystallized (FIG. 8 , right).

Example 2. Preparation of Pattern 1 crystalline form of amorphous 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

A polymorphic pattern of the amorphous 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate obtained in Example 1 was confirmed using various solvents (mainly ICH Class II and III).

A portion (each 10 mg) of ED01748-006-001-00 was dispensed into a vial, and an open vial was melted in a drying pistol (preheated at 110° C.) for 10 minutes under ambient pressure. The molten sample was removed, followed by rapid cooling with dry ice. The resulting amorphous glass material was treated with one solvent selected from acetone, chloroform, methanol (MeOH), tetrahydrofuran, diisopropyl ether, ethanol (EtOH), methyl ethyl ketone, acetonitrile, 2-propanol, tert-butanol, 1,2-dimethoxyethane (DME), 1-propanol, 2-butanol, water, 1,4-dioxane, 2-methyl-1-propanol, 2-methoxyethanol, butyl acetate, methyl butyl ketone, 3-methyl-1-butanol, 1-pentanol, cumene and anisole. The sample was shaken at room temperature for 2 to 3 hours, and then solvents except t-BuOH and 1,4-dioxane were transferred to a refrigerator. The other samples were stirred overnight at room temperature.

All solid samples were analyzed using an optical microscope and XRPD. In the experiment, most of the solutions were stored in a refrigerator for 2 days, and the remaining solutions were removed with CHCl₃ and anisole by evaporation at room temperature. CHCl₃ provided a solid rapidly dissolved by evaporating the resulting solution before isolation, and anisole provided a solid dissolved at room temperature before isolation, thereby obtaining a solid after partial evaporation. The residual solid obtained by evaporation was analyzed using an optical microscope and XRPD.

As a result, from most of the solvents, Pattern 1 or Pattern 3 was confirmed, Pattern 4 was confirmed from diethyl ether, a mixture of Pattern 1 and Pattern 3 was confirmed from chloroform and propyl acetate, Pattern 6 was confirmed from toluene and anisole, and a mixture of Pattern 3 and Pattern 6 was confirmed from benzonitrile. It was observed that the Pattern 6 material confirmed from toluene was converted to a mixture of Pattern 6 and Pattern 3 by XRPD. The Pattern 6 material confirmed from anisole stood overnight, and then converted to a mixture of Pattern 6 and Pattern 1 by XRPD. The various XRPD diffraction patterns obtained as above are shown in FIG. 9 .

Experimental Example 1 Analysis of Crystalline Form Pattern 1 (ED01748-006-001-00) of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate)

A crystalline form of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate (JBPOS0101/S-P-17001) obtained from Bio-Pharm Solutions Co. Ltd., analyzed by XRPD, is shown in FIG. 10 and Table 2 below, which is defined as Pattern 1.

TABLE 2 Angle d value Intensity Intensity Caption 2-Theta ° Angstrom Count % 6.662° 6.662 13.25637 275 40.7 7.392° 7.392 11.94899 132 19.6 8.153° 8.153 10.83624 179 26.5 9.801° 9.801 9.01695 219 32.4 11.303° 11.303 7.8224 351 52 11.660° 11.66 7.5835 357 52.9 12.068° 12.068 7.32802 66 9.8 12.874° 12.874 6.8707 144 21.3 13.280° 13.28 6.66182 675 100 13.435° 13.435 6.58531 496 73.5 13.913° 13.913 6.36017 271 40.1 14.703° 14.703 6.02005 434 64.3 15.256° 15.256 5.80305 135 20 16.243° 16.243 5.45254 467 69.2 16.948° 16.948 5.22742 415 61.5 17.796° 17.796 4.98008 99 14.7 18.266° 18.266 4.85289 101 15 18.572° 18.572 4.77361 119 17.6 19.091° 19.091 4.64505 382 56.6 19.419° 19.419 4.56748 420 62.2 19.895° 19.895 4.45926 226 33.5 20.443° 20.443 4.34088 254 37.6 21.124° 21.124 4.20246 184 27.3 22.076° 22.076 4.02326 131 19.4 22.354° 22.354 3.97388 240 35.6 22.673° 22.673 3.91877 184 27.3 23.174° 23.174 3.83509 198 29.3 23.582° 23.582 3.76964 224 33.2 24.202° 24.202 3.67451 303 44.9 24.619° 24.619 3.6132 319 47.3 25.260° 25.26 3.52298 271 40.1 25.435° 25.435 3.49906 279 41.3 25.932° 25.932 3.43308 307 45.5 26.138° 26.138 3.40653 230 34.1 26.614° 26.614 3.34669 248 36.7 26.983° 26.983 3.30175 268 39.7 27.965° 27.965 3.18799 243 36 28.256° 28.256 3.15585 161 23.9 28.805° 28.805 3.09686 234 34.7 28.998° 28.998 3.07672 289 42.8 29.319° 29.319 3.0438 206 30.5 29.690° 29.69 3.00656 180 26.7 30.247° 30.247 2.95246 229 33.9 30.483° 30.483 2.93017 192 28.4 31.697° 31.697 2.82066 228 33.8 32.668° 32.668 2.73894 140 20.7 33.414° 33.414 2.67953 121 17.9

The features of Pattern 1 were confirmed as follows.

TABLE 3 Pattern Features Pattern 1 Endothermic events of Onset 81° C. (anhydrous) (small amount) and 89° C. No mass loss in TGA upon decomposition. In polymorphic screening, can be obtained when various solvents were added to an amorphous form, and have partially improved crystallinity (ED01748-016-014-00 of MeCN, ED01748-016-010-00 of DIPE). No low temperature endothermic event.

The optical microscope images of the crystallized ED01748-006-001-00 Pattern 1 are shown in FIG. 11 . In addition, the ¹H NMR analysis result of the ED01748-006-001-00 corresponded to the structure shown in FIG. 12 . In addition, the UPLC purity was 98.6%, as determined by a UV detection chromatogram (FIG. 13 ).

In addition, as a result of thermal analysis of ED01748-006-001-00 by DSC, it was confirmed that a small endothermic reaction started at 81° C. (peak 82° C.), and an endothermic reaction started at 89° C. (peak 90° C.) corresponding to a melting temperature (FIG. 14 ).

In addition, at temperatures of about 200° C. or more, a broad peak corresponding to a mass loss observed by TGA through decomposition was shown at 229° C. TGA shows that 95% of the mass remained even at 237° C. without considerable mass loss until a temperature exceeded about 200° C. 100% of the mass was lost at 305° C. (FIG. 15 ).

From the GVS experiment result, the ED01748-006-001-00 also showed that the mass was increased by 0.14% in a range of 0 to 90% relative humidity (R.H.) like the isotherm plot of FIG. 16 . This means that a mass increase is insignificant, which shows storage stability by humidity is improved (FIGS. 16 and 17 ).

After the GVS experiment, there was no change in morphology observed from the XRPD result. When the ED01748-006-001-00 was stored under a stress condition of 40° C./75% RH or RT/97% RH, no change in morphology by XRPD was shown (FIG. 18 ). In addition, it was observed that the change in purity was 97.4% after 40° C./75% RH and 97.7% after RT/97% RH by UPLC (FIG. 19 ).

Experimental Example 2 Measurement of Solubility of Crystalline Form (ED01748-006-001-00) Pattern 1 of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate)

To measure the solubility of ED01748-006-001-00 Pattern 1, experiments were carried out in biological media (Fasted simulated gastric fluid (FaSSGF) and Fasted simulated intestinal fluid (FaSSIF)) at 37° C. 10 mL each of samples was dispersed into each of four vials, 1 mL each of FaSSGF and FaSSIF was added to each of the two vials and incubated in an orbital shaker for 24 hours. After incubation, all solids in each sample were dissolved, and the solubility was measured as follows.

TABLE 4 FaSSGF solubility FaSSIF solubility Sample after 24 h after 24 h ED01748-006-001-00 16.84 mg/mL 14.05 mg/mL

<Experimental Example 3> Confirmation of Thermodynamic Stability of Crystalline Form Pattern 1 of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate)

<3-1> Competitive Slurry Experiment for Pattern 1 and Pattern 3

To investigate the relative thermodynamic stability of various crystalline form patterns at room temperature and 50° C., competitive slurry experiments were carried out.

A mixture of Pattern 1 and Pattern 3 (ED01748-028-003-00, 4×20 mg) was dispensed into vials. They were treated with 250 μL of a saturated solution of Pattern 1 (ED01748-006-001-00) in DIPE or heptane (50 mg of ED01748-006-001-00 was treated with DIPE or heptane and heated at 50° C., a portion was removed as needed, and the resulting product was filtered through a 0.45 μm syringe filter, thereby forming a slurry). The produced slurry was stirred at room temperature or 50° C. A small sample was periodically removed and analyzed by XRPD, followed by monitoring the progress as shown in the following table. After analysis, the solid was returned to the vial, and an additional saturated solution was added as needed to maintain the slurry. After 4 days, the purity of the material was confirmed by UPLC. In both of DIPE samples, the purity was decreased to 98%, and in a heptane sample, the purity was 98.5%.

TABLE 5 Experiment Solvent Conditions Time Result ED01748-033-001 DIPE RT  1 day P1 ED01748-033-002 DIPE 50° C.  1 day P1 ED01748-033-003 Heptane RT  1 day P1 + P3 ED01748-033-004 Heptane 50° C.  1 day P1 + P3 ED01748-042-005 DIPE RT  4 days P1 ED01748-042-006 DIPE 50° C.  4 days P1 ED01748-042-007 Heptane RT  4 days P1 + P3 ED01748-042-008 Heptane 50° C.  4 days P1 ED01748-042-009 Heptane RT 11 days P1

The XRPD result of the material in this table is shown in FIG. 20 . In DIPE and heptane, both types of competitive slurries of the mixture of Pattern 1 and Pattern 3, which are anhydrous, were converted to Pattern 1 at room temperature and 50° C., and XRPD showed that no Pattern 3 remains. In heptane, the conversion to Pattern 1 was slower than that of DIPE, which is caused by a difference in solubility of materials. From the result, it was confirmed that Pattern 1 is more thermodynamically stable than Pattern 3.

3-2 Competitive Slurry Experiment for Pattern 1, Pattern 3, Pattern 6 and Pattern 11

A mixture of Pattern 1 and Pattern 3 (ED01748-028-003-00, 10 mg each) was dispensed into four vials, and Pattern 6 (ED01748-034-002-00, 5 mg) and Pattern 11 (ED01748-037-002-00, 5 mg) were added to respective vials. Each sample was treated with 300 μL of a filtered saturated solution of Pattern 1 (ED01748-006-001-00) prepared in DIPE or heptane. The resulting slurries were stirred at room temperature and 50° C. A small sample was periodically removed and analyzed by)(RFD, followed by monitoring as described in the following table.

After analysis, the solid was returned to the vial, and a saturated solution was additionally injected as needed to maintain the slurries. After 25 days, the purity of the solid material obtained in the heptane experiment was confirmed by UPLC, and no significant decrease in purity was shown by UPLC.

TABLE 6 Experiment Solvent Conditions Time Result ED01748-042-001 DIPE RT  1 day P1 ED01748-042-002 DIPE 50° C.  1 day P1 ED01748-042-003 Heptane RT  1 day P1 + P11 ED01748-042-004 Heptane 50° C.  1 day P1 + P11 ED01748-042-005 Heptane RT  5 days P1 + P11 ED01748-042-006 Heptane 50° C.  5 days P1 + P11 ED01748-042-007 Heptane RT 11 days P1 + P11 ED01748-042-008 Heptane 50° C. 11 days P1 + P11 ED01748-042-009 Heptane RT 25 days P1 + P11 ED01748-042-010 Heptane 50° C. 25 days P1 + P11

At room temperature and 50° C., after 1 day, all of the competitive slurries of the mixture of Pattern 1, Pattern 3, Pattern 6 and Pattern 11 materials in DIPE were converted to a Pattern 1 material. That is, it was confirmed that Pattern 1 is more thermodynamically stable than Pattern 3, Pattern 6 and Pattern 11 in DIPE at room temperature and 50° C. under the experimental conditions. In heptane, the mixture of Pattern 1 and Pattern 11 was present at room temperature and 50° C. after standing for 25 days, but no Pattern 6 remained. From this result, it was confirmed that Pattern 1 is more thermodynamically stable than Pattern 11 and Pattern 6 (FIGS. 21 and 22 ).

Example 3. Synthesis and Characterization of Crystalline Form Pattern 2 Crystalline of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

A portion of Pattern 1 (300 mg) was dissolved in 1,4-dioxane (4 mL) and filtered through a 0.45 μm syringe filter. The resultant solution was flash frozen in a dry ice/acetone bath and then lyophilized overnight to give Pattern 2 (98.6% UPLC purity).

XRPD analysis showed the material to be crystalline (FIG. 23A and Table 7 below) and consistent with the previous batch of Pattern 2 material prepared by lyophilization (ED01748-009-001-00).

DSC and TGA thermograms were also obtained for Pattern 2 of Formula 1 as shown in FIG. 23B and FIG. 23C, respectively. DSC shows an endothermic peak with an onset at 49° C. TGA shows about 9% weight loss between 58-191° C.

TABLE 7 XRPD Table of Pattern 2 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta ° Angstrom Count Intensity Intensity 1 6.654° 6.654 13.27325 585.2 503.3 34% 2 8.232° 8.232 10.73186 287.9 224.7 15% 3 8.414° 8.414 10.49984 275.6 212.2 14% 4 10.042° 10.042 8.8009 556.8 495.1 33% 5 11.884° 11.884 7.44125 104.5 40.7  3% 6 12.161° 12.161 7.271871 109.6 44.1  3% 7 12.889° 12.889 6.862837 94.7 24.2  2% 8 13.218° 13.218 6.692736 108.9 33.9  2% 9 14.014° 14.014 6.314321 406.9 319.0 21% 10 14.249° 14.249 6.210653 635.9 545.2 37% 11 14.609° 14.609 6.058375 132.8 38.6  3% 12 15.017° 15.017 5.894737 344.1 247.2 17% 13 16.266° 16.266 5.445024 1591.6 1484.5 100%  14 16.769° 16.769 5.282761 333.8 224.9 15% 15 19.342° 19.342 4.585368 1055.6 940.9 63% 16 19.827° 19.827 4.474214 751.9 635.0 43% 17 20.554° 20.555 4.317546 839.9 723.2 49% 18 20.931° 20.931 4.240818 184.7 69.8  5% 19 21.238° 21.238 4.180117 173.1 60.4  4% 20 21.945° 21.945 4.046983 183.1 68.3  5% 21 22.431° 22.431 3.96039 646.3 528.0 36% 22 23.022° 23.022 3.860039 261.1 141.0  9% 23 23.481° 23.481 3.785576 257.1 137.5  9% 24 23.683° 23.683 3.753747 371.2 252.4 17% 25 24.630° 24.63 3.611599 585.2 503.3  3% 26 25.175° 25.175 3.534629 167.6 45.2 36% 27 25.486° 25.486 3.492186 665.0 538.9 29% 28 25.809° 25.809 3.449146 558.9 431.8 45% 29 26.148° 26.148 3.405271 789.8 662.5 11% 30 26.500° 26.5 3.360755 293.5 166.9  4% 31 27.005° 27.005 3.299082 189.4 64.5 12% 32 28.119° 28.119 3.170902 292.2 171.4 30% 33 28.617° 28.617 3.116785 559.1 443.7 26% 34 28.941° 28.941 3.082644 503.8 391.1  4% 35 29.601° 29.601 3.01542 166.1 56.4 13% 36 29.894° 29.894 2.986496 294.1 189.6 19% 37 30.218° 30.218 2.955187 383.4 281.7 12% 38 30.837° 30.837 2.897335 280.3 182.5 14% 39 31.063° 31.063 2.876731 148.8 58.1  7% 40 31.658° 31.658 2.824047 195.6 107.2  2% 41 32.372° 32.372 2.763355 118.7 33.1 11% 42 32.931° 32.931 2.717684 251.2 163.5  3% 43 33.525° 33.525 2.670933 138.2 51.9  4% 44 34.547° 34.547 2.594185 135.3 53.1  5% 45 35.591° 35.591 2.520424 140.6 70.7  5% 46 36.026° 36.026 2.490971 130.4 68.2  3% 47 37.268° 37.268 2.410808 114.7 49.4  2% 48 37.636° 37.636 2.388055 93.5 24.4  2% 49 38.551° 38.551 2.333475 96.9 27.7  2% 50 40.101° 40.101 2.246761 92.4 23.8  7%

Example 4: Synthesis and Characterization of Crystalline Form Pattern 3 Crystalline of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

300 mg of Pattern 1 was placed into an open topped vial. This was placed in a drying pistol pre-heated to 110° C. and under ambient atmospheric conditions and heated at this temperature for 15 minutes. The molten material was then rapidly quench cooled by plunging into dry ice. The resultant glass was examined by optical microscopy and showed no evidence of crystalline material. This amorphous material was treated with heptane (2 mL). The glassy material did not dissolve. The resultant mixture was shaken at room temperature overnight and then a further 0.5 mL of heptane was added and some solid was gently scraped off the sides of the vial. There was still a small glassy region remaining at the base of the vial. After shaking for a further 4 hours at room temperature this had also crystallized. The solid was isolated by filtration and dried briefly under suction to give Pattern 3 (270 mg, 90%; 98.6% UPLC purity).

The XRPD pattern showed that Pattern 3 was crystalline (FIG. 24A and Table 8). DSC and TGA thermograms were also obtained for Pattern 3 of Formula 1 as shown in FIG. 24B and FIG. 24C, respectively. DSC shows an endothermic peak with an onset at 82° C. TGA shows no significant mass loss until decomposition above about 210° C.

TABLE 8 XRPD Table of Pattern 3 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom Count Intensity Intensity 1 6.336° 6.336 13.93926 744.9 636.4  14% 2 6.621° 6.621 13.33832 147.4 47.6  1% 3 7.718° 7.718 11.44593 362.6 285.4  6% 4 8.914° 8.914 9.912663 2184.1 2104.4  45% 5 9.481° 9.481 9.320601 522.5 444.9  10% 6 9.849° 9.849 8.973114 350.9 277.1  6% 7 10.079° 10.079 8.769467 134.0 63.4  1% 8 10.919° 10.919 8.095963 2971.3 2902.6  62% 9 12.104° 12.104 7.306362 148.2 82.9  2% 10 12.632° 12.632 7.001914 234.0 167.8  4% 11 13.381° 13.381 6.61166 2223.3 2156.3  46% 12 14.266° 14.266 6.203578 118.5 60.3  1% 13 15.155° 15.155 5.84165 918.1 846.1  18% 14 15.800° 15.8 5.604529 4749.3 4667.6 100% 15 16.087° 16.087 5.505167 286.4 202.2  4% 16 17.022° 17.022 5.204755 1397.7 1304.8  28% 17 17.507° 17.507 5.061515 1341.5 1243.0  27% 18 17.816° 17.816 4.974424 4329.8 4229.5  91% 19 18.346° 18.346 4.831913 163.7 63.2  1% 20 18.718° 18.718 4.736824 296.0 195.3  4% 21 18.968° 18.968 4.67485 648.1 547.5  12% 22 19.290° 19.29 4.597661 345.2 246.1  5% 23 19.842° 19.842 4.470953 1094.9 1001.6  21% 24 20.903° 20.903 4.246267 138.3 65.8  1% 25 21.913° 21.913 4.052833 383.1 312.5  7% 26 22.247° 22.247 3.992831 132.6 57.2  1% 27 23.162° 23.162 3.837123 1128.3 1043.7  22% 28 23.529° 23.529 3.777981 444.4 358.2  8% 29 23.800° 23.8 3.735555 432.4 346.3  7% 30 24.023° 24.023 3.701461 744.9 636.4  21% 31 24.625° 24.625 3.61233 1056.7 971.4  2% 32 24.936° 24.936 3.567931 184.8 104.4  4% 33 25.309° 25.309 3.516192 265.0 187.8  3% 34 26.031° 26.031 3.420315 227.5 156.0  4% 35 26.836° 26.836 3.319469 276.1 208.6  7% 36 27.154° 27.154 3.281378 382.4 305.5  2% 37 27.719° 27.719 3.215742 152.6 70.2  27% 38 28.240° 28.24 3.157599 1339.2 1250.3  18% 39 28.658° 28.658 3.112448 941.9 851.0  2% 40 28.919° 28.919 3.084961 200.7 110.8  1% 41 29.296° 29.296 3.046102 141.0 53.1  4% 42 29.590° 29.59 3.016512 269.3 183.6  6% 43 30.355° 30.355 2.942188 382.1 296.8  17% 44 30.753° 30.753 2.905053 860.2 778.1  12% 45 31.133° 31.133 2.87042 621.2 539.9  4% 46 31.877° 31.877 2.805122 256.5 178.0  4% 47 32.417° 32.417 2.759587 264.2 193.0  3% 48 32.982° 32.982 2.713599 187.8 118.6  3% 49 33.655° 33.655 2.660844 201.6 138.8  1% 50 34.350° 34.35 2.608626 116.0 56.0  1% 51 35.111° 35.111 2.553829 105.9 46.0  1% 52 35.390° 35.39 2.534331 105.0 46.4  1% 53 36.918° 36.918 2.43287 85.4 26.7  4% 54 37.562° 37.562 2.392611 238.8 180.3  3% 55 38.494° 38.494 2.336757 186.9 127.5  2% 56 38.734° 38.734 2.322875 162.2 96.7  3% 57 39.410° 39.41 2.284549 189.8 123.3  3% 58 39.902° 39.902 2.257527 195.0 129.7  1% 59 41.017° 41.017 2.198692 87.4 26.9  1% 60 41.790° 41.79 2.159796 87.8 39.9  1%

Example 5: Synthesis and Characterization of Crystalline Form Pattern 4 Crystalline of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

300 mg of Pattern 1 was placed into an open topped vial. This was placed in a drying pistol pre-heated to 110° C. and under ambient atmospheric conditions and heated at this temperature for 12 minutes. The molten material was then rapidly quench cooled by plunging into dry ice. The resultant glass was examined by optical microscopy and showed no evidence of crystalline material. This amorphous material was treated with diethyl ether (1.5 mL) to give a solution and shaken at room temperature overnight. As no crystals were observed the solution was transferred to the refrigerator and left to stand overnight and Pattern 4 formed. The XRPD pattern of Pattern 4 is shown in FIG. 25A and Table 9.

The remainder of the material was isolated by brief filtration under a stream of nitrogen. It gave a sticky solid which was consistent by XRPD with Pattern 4. Brief drying of this sticky material whilst standing in the open vial gave less sticky material which showed a change in form by XRPD from Pattern 4 to a mixture of Pattern 1 and Pattern 3 by XRPD (98.3% UPLC purity). DSC thermogram was obtained as shown in FIG. 25B. DSC shows an endothermic peak with an onset at 81° C. and 88° C. consistent with a mixture of Pattern 1+Pattern 3.

TABLE 9 XRPD Table of Pattern 4 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom Count Intensity Intensity 1 6.904° 6.904 12.79366 694.2 580.1  27% 2 8.636° 8.636 10.23091 2192.8 2118.2 100% 3 9.969° 9.969 8.865413 389.8 312.9  15% 4 11.921° 11.921 7.418169 427.1 348.4  16% 5 12.867° 12.868 6.874347 568.1 477.8  23% 6 13.428° 13.428 6.588633 988.6 888.4  42% 7 13.653° 13.653 6.480419 2027.0 1923.6  91% 8 14.717° 14.717 6.014249 220.0 108.1  5% 9 15.035° 15.035 5.88803 403.8 291.3  14% 10 15.627° 15.627 5.665976 357.1 246.2  12% 11 16.949° 16.949 5.226864 568.4 455.7  22% 12 17.245° 17.245 5.138061 1526.0 1413.4  67% 13 17.391° 17.391 5.09524 2004.2 1891.9  89% 14 19.570° 19.570 4.532434 582.8 473.5  22% 15 20.117° 20.117 4.410478 1007.3 895.7  42% 16 20.428° 20.428 4.344045 268.3 156.7  7% 17 20.668° 20.668 4.294188 175.1 64.1  3% 18 21.257° 21.257 4.176502 445.6 335.3  16% 19 21.690° 21.690 4.09407 264.6 154.8  7% 20 22.071° 22.071 4.02422 203.5 95.4  5% 21 23.797° 23.797 3.736009 252.9 136.6  16% 22 24.161° 24.161 3.680669 237.3 118.0  6% 23 25.382° 25.382 3.506276 893.6 763.1  36% 24 25.727° 25.727 3.460072 350.4 216.5  10% 25 26.137° 26.137 3.406705 697.9 561.5  27% 26 26.838° 26.838 3.319255 936.0 798.7  38% 27 27.333° 27.333 3.26021 219.2 84.1  4% 28 27.986° 27.986 3.185643 515.3 382.5  18% 29 28.456° 28.456 3.134095 1930.1 1800.1  85% 30 29.089° 29.089 3.067292 746.7 623.8  29% 31 29.540° 29.540 3.021475 435.6 320.0  15% 32 31.429° 31.429 2.844048 157.5 65.3  3% 33 31.574° 31.574 2.831377 160.4 68.2  3% 34 32.096° 32.096 2.78644 606.7 516.1  24% 35 32.377° 32.377 2.762932 457.5 368.9  17% 36 33.797° 33.797 2.65003 332.0 247.8  12% 37 34.317° 34.317 2.611056 186.6 101.7  15% 38 35.038° 35.038 2.55894 155.4 73.7  3% 39 35.400° 35.400 2.533632 412.5 334.2  16% 40 36.922° 36.922 2.43257 125.4 53.5  3% 41 38.004° 38.004 2.36579 153.4 84.8  4% 42 38.989° 38.989 2.308263 92.7 25.1  1% 43 40.093° 40.093 2.24719 136.1 64.8  3% 44 40.751° 40.751 2.212412 185.4 112.8  5% 45 41.250° 41.250 2.186823 161.3 90.4  4%

Example 6: Synthesis and Characterization of Crystalline Form Pattern 5 Crystalline of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

Pattern 5 was obtained from chloroform or propyl acetate. Pattern 5 was assigned as a mixture of Pattern 1 and Pattern 3.

Experiment Solvent Volume/uL Observations Notes Pattern 1 chloroform 50 Soluble Refrigerated, Pattern 5 or Mix Pattern gave solid, 1 + Pattern 3 which rapidly dissolved at RT. evaporated 2 propyl acetate 50 Soluble Refrigerated, Pattern 5 or Pattern 1 + evaporated Pattern 3 mixture. No change on standing overnight

The XRPD pattern showed that Pattern 5 was crystalline (FIG. 26A and Table 10).

DSC and TGA thermograms were obtained as shown in FIG. 26B and FIG. 26C. DSC shows an endothermic peak with an onset of 59° C. (very small), 81° C. and 89° C. TGA shows no significant mass loss until decomposition.

TABLE 10 XRPD Table of Pattern 5 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom Counts Intensity Intensity 1 6.288° 6.288 14.04477 410.9 294.4  26% 2 6.591° 6.591 13.40072 448.3 341.2  30% 3 7.299° 7.299 12.1017 173.5 84.7  8% 4 7.669° 7.669 11.5183 142.7 58.3  5% 5 8.045° 8.045 10.98169 208.1 127.0  11% 6 8.396° 8.396 10.52315 146.1 67.4  6% 7 8.858° 8.858 9.975244 801.7 727.4  65% 8 9.427° 9.427 9.374208 229.8 162.6  14% 9 9.736° 9.736 9.077063 281.1 218.7  19% 10 9.972° 9.972 8.863215 315.5 257.2  23% 11 10.865° 10.865 8.136434 907.7 853.5  76% 12 11.198° 11.198 7.895094 313.0 258.5  23% 13 11.564° 11.564 7.646404 304.3 250.4  22% 14 12.017° 12.017 7.358904 90.3 38.5  3% 15 12.586° 12.586 7.027328 129.6 76.3  7% 16 13.178° 13.178 6.713122 615.3 554.8  49% 17 13.335° 13.335 6.634624 973.3 911.3  81% 18 13.818° 13.818 6.403406 210.1 144.4  13% 19 14.626° 14.626 6.051351 317.6 249.7  22% 20 15.112° 15.112 5.857883 293.5 226.1  20% 21 15.754° 15.754 5.620764 1088.1 1021.3  91% 22 16.152° 16.152 5.483039 376.9 310.8  28% 23 16.977° 16.977 5.218423 464.4 394.2  35% 24 17.462° 17.462 5.074476 427.9 353.6  31% 25 17.767° 17.767 4.988079 1203.0 1126.9 100% 26 18.970° 18.970 4.674501 296.9 214.3  19% 27 19.349° 19.349 4.583826 408.7 325.5  29% 28 19.797° 19.797 4.48099 842.9 760.2  67% 29 20.354° 20.354 4.359617 180.5 100.5  9% 30 20.925° 20.925 4.241933 119.6 44.6  4% 31 21.859° 21.859 4.062715 151.2 83.0  7% 32 22.232° 22.232 3.995424 158.5 86.8  8% 33 22.581° 22.581 3.934432 128.7 54.8  5% 34 23.104° 23.104 3.84653 342.2 265.9  24% 35 23.460° 23.460 3.789058 254.7 177.5  16% 36 23.776° 23.776 3.739354 354.2 277.0  25% 37 23.974° 23.974 3.70888 352.6 275.8  24% 38 24.573° 24.573 3.619826 209.0 131.7  12% 39 24.904° 24.904 3.572441 210.4 131.1  12% 40 25.158° 25.158 3.536991 204.5 124.1  11% 41 25.979° 25.979 3.427044 250.5 168.7  15% 42 26.546° 26.546 3.355137 128.8 46.7  4% 43 26.861° 26.861 3.31641 161.0 79.3  7% 44 27.092° 27.092 3.288682 168.6 87.7  8% 45 27.334° 27.334 3.260165 111.3 31.7  3% 46 27.666° 27.666 3.221733 322.5 243.5  22% 47 28.197° 28.197 3.162233 409.9 330.5  29% 48 28.860° 28.860 3.091091 140.6 63.5  6% 49 29.245° 29.245 3.051331 229.9 155.4  14% 50 29.532° 29.532 3.022331 236.9 165.1  15% 51 30.312° 30.312 2.94627 251.0 182.4  16% 52 30.712° 30.712 2.908782 186.0 117.7  10% 53 30.993° 30.993 2.883035 125.7 58.4  5% 54 31.796° 31.796 2.812095 128.8 65.4  6% 55 32.341° 32.341 2.76595 99.8 40.9  4% 56 32.971° 32.971 2.71448 72.9 20.0  2% 57 33.855° 33.855 2.645633 69.3 20.7  2% 58 36.055° 36.055 2.489096 65.7 22.2  2% 59 36.620° 36.620 2.45197 72.5 29.6  3% 60 38.414° 38.414 2.341442 71.0 27.7  2% 61 39.853° 39.853 2.260157 62.5 22.2  2%

Example 7: Synthesis and Characterization of Crystalline Form Pattern 6 Crystalline of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

200 mg of Pattern 1 was placed into an open topped vial. This was placed in a drying pistol pre-heated to 110° C. and under ambient atmospheric conditions and heated at this temperature for 15 minutes. The molten material was then rapidly quench cooled by plunging into dry ice. The resultant glass was examined by optical microscopy and showed no evidence of crystalline material. This amorphous material was treated with toluene (4 mL) and shaken at room temperature. After 4 days solid had formed on the base of the vial. Pattern 6 was isolated by brief filtration under a stream of nitrogen (90.2% UPLC purity).

The XRPD pattern showed that Pattern 6 was crystalline (FIG. 27A and Table 11). DSC and TGA thermograms were also obtained for Pattern 6 of Formula 1 as shown in FIG. 27B and FIG. 27C, respectively. DSC shows an endothermic peak with an onset at 72° C. TGA shows 4.8% weight percent loss between 70-161° C.

TABLE 11 10.0 XRPD Table of Pattern 6 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom Counts Intensity Intensity 1 6.629° 6.629 13.32261 1734.8 1643.9  56% 2 8.289° 8.289 10.65854 1245.4 1179.0  40% 3 8.974° 8.974 9.846114 88.9 29.8  1% 4 9.958° 9.958 8.875217 1618.7 1559.6  53% 5 11.980° 11.980 7.381588 393.6 334.1  11% 6 13.225° 13.225 6.689138 219.7 158.7  5% 7 14.131° 14.131 6.262249 1632.7 1566.0  53% 8 14.936° 14.936 5.926644 397.7 331.5  11% 9 15.982° 15.982 5.540995 97.9 32.3  1% 10 16.374° 16.374 5.409378 3004.1 2935.9 100% 11 16.576° 16.576 5.343692 926.9 858.0  29% 12 19.285° 19.285 4.598821 1179.5 1104.8  38% 13 19.882° 19.882 4.462 1356.2 1279.8  44% 14 20.529° 20.529 4.32277 988.2 914.3  31% 15 21.017° 21.017 4.223648 262.5 193.6  7% 16 21.878° 21.878 4.059192 124.6 56.9  2% 17 22.482° 22.482 3.951522 604.4 531.4  18% 18 22.836° 22.836 3.891081 168.8 94.7  3% 19 23.559° 23.559 3.773296 349.5 277.3  9% 20 24.023° 24.023 3.701401 161.1 93.1  3% 21 24.918° 24.918 3.570469 259.2 191.7  7% 22 25.072° 25.072 3.548931 536.0 466.1  16% 23 25.623° 25.623 3.473757 801.2 725.0  25% 24 25.921° 25.921 3.434617 893.8 815.5  28% 25 26.602° 26.602 3.348142 225.8 145.8  5% 26 27.003° 27.003 3.299365 243.9 164.7  6% 27 27.925° 27.925 3.192473 213.0 130.8  4% 28 28.422° 28.422 3.137742 1298.1 1214.3  41% 29 28.833° 28.833 3.094014 164.6 81.6  3% 30 29.659° 29.659 3.009618 527.2 447.1  15% 31 30.055° 30.055 2.970896 147.0 68.4  2% 32 30.715° 30.715 2.908536 548.7 476.4  16% 33 31.916° 31.916 2.801745 151.6 86.9  3% 34 32.328° 32.328 2.767 278.5 212.6  7% 35 33.070° 33.070 2.706611 133.8 69.3  2% 36 33.525° 33.525 2.670882 131.6 70.5  2% 37 33.783° 33.783 2.651092 173.2 115.1  4% 38 34.973° 34.973 2.563588 145.7 84.9  3% 39 35.716° 35.716 2.511899 84.1 23.2  1% 40 36.898° 36.898 2.434115 136.8 74.1  3% 41 38.265° 38.265 2.350248 78.2 24.1  1% 42 38.935° 38.935 2.311308 86.8 32.1  1% 43 39.979° 39.979 2.253317 109.1 48.9  2% 44 40.371° 40.371 2.232336 135.3 75.5  3% 45 40.644° 40.644 2.217998 144.6 86.0  3%

Example 8: Solvent/Antisolvent Polymorph Screening for Pattern 1

TABLE A Volume/ Volume/ Initial Exp. Solvent ul Anti-Solvent ul result Notes Result 1 2-propanol 60 Toluene 100 Soluble Shaken RT, Soluble refrigerated 2 2-propanol 60 Heptane 200 Soluble Shaken RT, Soluble refrigerated 3 2-propanol 60 Diethyl ether 100 Soluble Shaken RT, Soluble refrigerated, 4 2-propanol 60 TBME 200 Soluble Shaken RT, Soluble refrigerated, 5 acetone 60 Toluene 100 Soluble Shaken RT, Soluble refrigerated 6 acetone 60 Heptane 175 Cloudy oil oil 7 acetone 60 Diethyl ether 100 Soluble Shaken RT, Soluble refrigerated 8 acetone 60 TBME 100 Soluble Shaken RT, Soluble refrigerated 9 chloroform 60 Toluene 100 Precipitate Shaken RT, Crystalline solid XRPD Pattern 9 No change on standing o/n 10 chloroform 60 Heptane 25 Precipitate Shaken RT, Crystalline solid XRPD Pattern 8 No change on standing o/n 11 chloroform 60 Diethyl ether 100 Soluble Shaken RT, Soluble refrigerated 12 chloroform 60 TBME 100 Soluble Shaken RT, Soluble refrigerated 13 DCM 80 Toluene 100 Precipitate Shaken RT, Crystalline solid XRPD Pattern 9 No change on standing o/n 14 DCM 80 Heptane 50 Precipitate Shaken RT, Crystalline solid XRPD Pattern 8 Small change on standing o/n 14 DCM 80 Diethyl ether 100 Soluble Shaken RT, Soluble refrigerated, 16 DCM 80 TBME 100 Soluble Shaken RT, Soluble refrigerated ethyl acetate 60 Toluene 100 Soluble Shaken RT, Soluble refrigerated 18 ethyl acetate 60 Heptane 100 Cloudy Oil, then Crystalline solid formed Pattern 11 Change on standing (5 days) to mix P2 + P3 19 ethyl acetate 60 Diethyl ether 100 Soluble Shaken RT, Soluble refrigerated 20 ethyl acetate 60 TBME 100 Soluble Shaken RT, Soluble refrigerated 21 ethyl acetate 60 Pentane 225 Cloudy Oil Oil 22 ethyl acetate 60 cyclohexane 350 Precipitate Shaken RT, Crystalline, solid XRPD P1 23 ethyl acetate 60 methylcyclo- 325 Precipitate Shaken RT, Crystalline, hexane solid XRPD P1 24 chloroform 60 Pentane 75 Precipitate Shaken RT, Crystalline solid XRPD P8, change on standing 25 chloroform 60 cyclohexane 125 Precipitate Shaken RT, Crystalline solid XRPD P7. Change on standing 26 chloroform 60 methylcyclo- 75 Precipitate Shaken RT, Crystalline hexane solid XRPD P7, No change on standing 27 DCM 80 Pentane 100 Precipitate Shaken RT, Crystalline solid XRPD P8. Change on standing 28 DCM 80 cyclohexane 50 Precipitate Shaken RT, Crystalline solid XRPD P7. No change on standing 29 DCM 80 methylcyclo- 50 Precipitate Shaken RT, Crystalline hexane solid XRPD P7. Change on standing

Pattern 7 was obtained from DCM/cyclohexane, DCM/methylcyclohexane, CHCl₃/cyclohexane and CHCl₃/methylcyclohexane in the solvent/anti-solvent screening experiment described in Table A.

The XRPD pattern for Pattern 7 is shown in FIG. 28A and Table 12. DSC and TGA thermograms were also obtained for Pattern 7 of Formula 1 as shown in FIG. 28B and FIG. 28C, respectively. DSC of freshly isolated Pattern 7 shows endothermic peaks with an onset at 58° C. and 86° C. The TGA shows about a 4% weight percent loss between about 54 and 87° C.

TABLE 12 XRPD Table of Pattern 7 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom Count Intensity Intensity 1 6.678° 6.678 13.22453 182.7 66.5  1% 2 8.373° 8.373 10.55194 119.9 55.3  1% 3 9.048° 9.048 9.765502 120.4 63.5  1% 4 10.006° 10.006 8.8328 6839.3 6771.9 100% 5 11.869° 11.869 7.450305 106.3 43.5  1% 6 12.143° 12.143 7.282938 89.9 30.1  0% 7 13.535° 13.535 6.536877 91.0 35.0  1% 8 14.321° 14.321 6.179873 142.5 74.9  1% 9 14.994° 14.994 5.903751 3424.6 3349.5  49% 10 15.838° 15.838 5.59096 106.2 29.4  0% 11 16.273° 16.273 5.442454 2107.7 2032.5  30% 12 16.814° 16.814 5.268797 146.1 77.3  1% 13 19.351° 19.351 4.583279 107.0 43.5  1% 14 20.003° 20.003 4.435391 1524.3 1453.1  21% 15 20.958° 20.958 4.23527 212.9 143.2  2% 16 21.249° 21.249 4.177896 494.3 428.1  6% 17 23.005° 23.005 3.862903 81.0 29.5  0% 18 23.811° 23.811 3.733878 84.2 34.3  1% 19 24.320° 24.32 3.656892 78.6 26.4  0% 20 25.077° 25.077 3.548254 541.4 477.8  7% 21 25.813° 25.813 3.448667 1087.2 1015.6  15% 22 26.097° 26.097 3.411779 139.2 66.8  1% 23 26.683° 26.683 3.338122 115.8 46.2  1% 24 28.214° 28.214 3.160371 310.1 243.1  4% 25 28.742° 28.742 3.103599 146.5 78.7  1% 26 29.633° 29.633 3.012272 112.5 39.8  1% 27 30.173° 30.173 2.959586 475.6 396.3  6% 28 30.780° 30.78 2.90252 378.1 297.3  4% 29 31.075° 31.075 2.875691 1796.1 1716.8  25% 30 32.762° 32.762 2.731355 106.3 38.9  1% 31 33.382° 33.382 2.682026 166.0 100.2  1% 32 36.132° 36.132 2.483912 98.8 48.0  1% 33 37.587° 37.587 2.391073 69.9 25.7  0% 34 38.199° 38.199 2.354154 98.4 52.7  1% 35 40.267° 40.267 2.237886 89.2 39.8  1% 36 40.582° 40.582 2.221247 238.9 189.0  3%

Pattern 8 was obtained from DCM/heptane, DCM/pentane, CHCl₃/heptane and CHCl₃/pentane in the solvent/anti-solvent screening experiment described in Table A.

The XRPD pattern for Pattern 8 is shown in FIG. 29A. and Table 13. Pattern 8 from chloroform and heptane was observed to change on standing. The thermal behaviour in the DSC was observed to change as shown in the DSC overlay in FIG. 29B. The material after standing for 4 days showed endothermic events of onset 68° C., 82° C. and 88° C. This is consistent with a mixture containing some Pattern 3. There seems to be some conversion to Pattern 1 in the DSC. The freshly isolated sample showed broader unresolved and overlapping endothermic events of onset 74° C. (between 61-85° C.) The TGA thermogram as seen in FIG. 29C of this freshly isolated material shows a 4.4% mass loss between 64-123° C. and the sample after standing shows a mass loss of 3.7% between 66-113° C. suggesting both are solvated or hydrated forms with some solvent being lost during the conversion.

TABLE 13 XRPD Table of Pattern 8 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom count Intensity Intensity 1 6.610° 6.61 13.36227 545.6 434.2  8% 2 8.216° 8.216 10.7535 208.5 142.6  3% 3 8.450° 8.45 10.45576 295.2 231.8  4% 4 9.045° 9.045 9.76876 111.2 54.4  1% 5 10.005° 10.005 8.833625 5412.0 5348.1 100% 6 11.826° 11.826 7.477503 149.6 85.1  2% 7 12.172° 12.172 7.26558 119.6 60.5  1% 8 13.262° 13.262 6.670907 72.4 22.8  0% 9 13.515° 13.515 6.546331 79.6 28.6  1% 10 14.039° 14.039 6.303211 159.5 103.9  2% 11 14.316° 14.316 6.181698 269.1 209.6  4% 12 14.990° 14.99 5.905528 2329.1 2264.9  42% 13 15.754° 15.754 5.620678 126.3 60.9  1% 14 16.235° 16.235 5.455233 2573.6 2507.5  47% 15 16.853° 16.853 5.256468 263.7 201.7  4% 16 19.307° 19.307 4.593502 224.0 166.2  3% 17 20.008° 20.008 4.434152 955.7 889.5  17% 18 20.476° 20.476 4.334008 207.3 139.5  3% 19 20.675° 20.675 4.292601 177.8 110.4  2% 20 20.927° 20.927 4.241448 198.4 132.1  2% 21 21.291° 21.291 4.169857 508.5 445.7  8% 22 22.460° 22.46 3.955396 143.2 91.4  2% 23 22.965° 22.965 3.869515 98.6 48.6  1% 24 23.714° 23.714 3.749011 128.7 80.0  1% 25 24.396° 24.396 3.645681 110.6 55.7  1% 26 25.107° 25.107 3.544069 466.4 403.6  18% 27 25.427° 25.427 3.500138 212.6 146.6  3% 28 25.787° 25.787 3.452086 909.4 841.5  16% 29 26.147° 26.147 3.405425 150.6 82.8  2% 30 26.603° 26.603 3.348019 150.5 85.0  2% 31 28.116° 28.116 3.171172 449.8 387.6  7% 32 28.783° 28.783 3.099194 292.1 227.9  4% 33 29.562° 29.562 3.019279 152.5 84.9  2% 34 29.934° 29.934 2.982634 117.2 45.9  1% 35 30.215° 30.215 2.95548 267.6 194.9  4% 36 30.766° 30.766 2.903811 283.8 211.8  4% 37 31.132° 31.132 2.870564 1201.0 1131.8  21% 38 32.199° 32.199 2.777786 86.2 30.3  1% 39 32.708° 32.708 2.735745 181.7 123.1  2% 40 33.088° 33.088 2.705182 96.9 38.7  1% 41 33.467° 33.467 2.675392 166.3 109.7  2% 42 33.978° 33.978 2.636339 79.9 27.9  1% 43 36.208° 36.208 2.47891 107.5 60.1  1% 44 37.547° 37.547 2.393519 77.7 33.3  1% 45 38.297° 38.297 2.34836 102.0 57.4  1% 46 40.070° |40.07 2.248458 69.9 21.7  0% 47 40.385° 40.385 2.231636 141.0 92.0  2% 48 40.623° 40.623 2.219077 175.1 126.5  2%

Pattern 9 was obtained from DCM/toluene, CHCl₃/toluene in the solvent/anti-solvent screening experiment described in Table A.

The XRPD pattern for Pattern 9 is shown in FIG. 30A. and Table 14. As shown in FIG. 30B DSC of Pattern 9 shows endothermic peaks with an onset at about 63° C., 81° C. and 88° C.

TABLE 14 XRPD Table of Pattern 9 of Formula 1 Angle 2 d Value Intensity Net Rel Index Caption Theta° Angstrom Count Intensity Intensity 1 6.690° 6.690 13.20243 447.0 336.9  3% 2 8.359° 8.359 10.56867 561.9 495.3  4% 3 9.078° 9.078 9.733361 113.2 50.0  0% 4 10.043° 10.043 8.80074 5895.8 5816.4  51% 5 12.013° 12.013 7.361348 631.8 562.7  5% 6 13.581° 13.581 6.514763 88.8 32.7  0% 7 14.219° 14.219 6.223952 510.6 448.8  4% 8 15.023° 15.023 5.892425 1782.2 1712.4  15% 9 16.413° 16.413 5.396596 11448.0 11358.9 100% 10 19.384° 19.384 4.575548 122.6 49.8  0% 11 20.015° 20.015 4.432676 1098.1 1020.8  9% 12 20.592° 20.592 4.309692 261.1 187.0  2% 13 21.104° 21.104 4.206413 840.4 775.2  7% 14 22.538° 22.538 3.941785 101.1 48.7  0% 15 23.370° 23.370 3.803311 100.2 50.2  0% 16 24.040° 24.040 3.698828 308.1 259.4  2% 17 25.083° 25.083 3.547366 477.5 408.7  4% 18 25.940° 25.940 3.432096 4235.7 4151.4  37% 19 26.663° 26.663 3.340634 131.9 46.9  0% 20 27.095° 27.095 3.288367 107.4 27.2  0% 21 28.406° 28.406 3.139458 2206.7 2123.6  19% 22 29.004° 29.004 3.076145 110.6 34.7  0% 23 29.727° 29.727 3.002909 164.5 84.5  1% 24 30.173° 30.173 2.959532 461.7 379.1  3% 25 30.917° 30.917 2.889966 1522.0 1444.7  13% 26 32.296° 32.296 2.769679 101.4 35.7  0% 27 33.041° 33.041 2.708896 461.8 397.1  3% 28 33.493° 33.493 2.67334 171.6 108.0  1% 29 33.908° 33.908 2.641598 104.5 45.9  0% 30 35.034° 35.034 2.559219 106.5 51.0  0% 31 36.364° 36.364 2.468625 134.9 81.3  1% 32 36.819° 36.819 2.439171 147.1 94.6  1% 33 37.862° 37.862 2.374294 103.1 52.3  0% 34 40.625° 40.625 2.219007 331.5 274.1  2% 35 40.793° 40.793 2.210219 289.1 232.0  2%

Pattern 8 was obtained from DCM/heptane, DCM/pentane, CHCl₃/heptane and CHCl₃/pentane in the solvent/anti-solvent screening experiment described in Table A.

Pattern 7 and Pattern 8 are similar in showing variable behaviour on standing.

The XRPD pattern for Pattern 8 is shown in FIG. 29A. As shown in FIG. 29B DSC of freshly isolated crystalline Pattern 8 of Formula 1 exhibits an endothermic peak with an onset at 74° C.). As shown in the TGA of freshly isolated crystalline Pattern 8 of Formula 1 exhibits an about 4.4% (wt %) loss between about 64° C. to about 123° C.

Example 9: Synthesis and Characterization of Crystalline Form Pattern 10 Crystalline of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

300 mg of Pattern 1 was placed into an open topped vial. This was placed in a drying pistol pre-heated to 110° C. and under ambient atmospheric conditions and heated at this temperature for 15 minutes. The molten material was then rapidly quench cooled by plunging into dry ice. The resultant glass was examined by optical microscopy and showed no evidence of crystalline material. This amorphous material was treated with acetonitrile (1.5 mL) to give a solution, shaken at room temperature for 30 minutes, refrigerated for 3 days and then allowed to evaporate at room temperature overnight under ambient conditions. XRPD analysis of the resulting crystalline form was consistent with Pattern 1 together with some extra peaks. These extra peaks were no longer evident upon reanalysis of the sample after standing overnight on the XRPD disc. This behavior is indicative of the presence of another albeit transient Pattern which is potentially an acetonitrile solvate.

The remainder of the material was treated with acetonitrile (1 mL) and the slurry shaken at room temperature overnight. A portion of this material was removed and analyzed rapidly by XRPD (FIG. 31A and Table 15). It showed the formation of a new Pattern, designated Pattern 10, which corresponds to the extra peaks observed in the initial scale up sample, together with some Pattern 1.

TABLE 15 XRPD Table of Pattern 10 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom Count Intensity Intensity 1 7.389° 7.389 11.95375 184.4 114.6  4% 2 11.906° 11.906 7.427009 1394.0 1335.8  52% 3 12.623° 12.623 7.007071 144.7 79.9  3% 4 13.441° 13.441 6.582259 1202.3 1128.0  44% 5 14.140° 14.140 6.258653 722.6 642.0  25% 6 14.657° 14.657 6.038925 1494.0 1410.5  55% 7 15.760° 15.760 5.618697 221.7 139.2  5% 8 16.554° 16.554 5.350962 821.4 741.0  29% 9 16.885° 16.885 5.246759 220.8 142.6  6% 10 18.493° 18.493 4.793934 283.5 208.7  8% 11 18.979° 18.979 4.672309 154.1 75.9  3% 12 19.826° 19.826 4.474541 155.6 74.5  3% 13 21.512° 21.512 4.127553 157.9 75.3  3% 14 22.118° 22.118 4.01574 490.1 401.1  16% 15 22.549° 22.549 3.940006 691.3 596.8  23% 16 22.801° 22.801 3.897017 338.4 241.5  9% 17 23.734° 23.734 3.74581 261.9 150.4  6% 18 24.445° 24.445 3.638554 398.4 277.0  11% 19 24.706° 24.706 3.600659 2625.0 2501.3  98% 20 25.135° 25.135 3.540104 492.8 366.8  14% 21 25.877° 25.877 3.440297 227.2 101.9  4% 22 26.587° 26.587 3.349975 261.7 140.7  6% 23 26.909° 26.909 3.310645 2665.4 2547.2 100% 24 28.049° 28.049 3.178655 141.4 33.8  1% 25 28.362° 28.362 3.144217 285.3 179.2  7% 26 29.105° 29.105 3.065613 211.5 112.0  4% 27 29.416° 29.416 3.034005 1207.0 1111.4  44% 28 31.619° 31.619 2.827397 232.2 158.3  6% 29 33.924° 33.924 2.64037 119.6 55.8  2% 30 35.423° 35.423 2.532039 100.6 36.5  1% 31 35.799° 35.799 2.506281 197.6 134.5  5% 32 36.939° 36.939 2.431494 298.0 235.8  19% 33 37.329° 37.329 2.407008 122.7 61.9  2% 34 38.836° 38.836 2.316971 389.7 324.1  13% 35 40.400° 40.400 2.230819 184.8 118.4  5%

Example 10: Synthesis and Characterization of Crystalline Form Pattern 11 Crystalline of 1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate

A portion of Pattern 1 (300 mg) was dissolved in ethyl acetate (1 mL) and then heptane (1.75 mL) was added portion wise until the mixture remained cloudy. An oily layer formed at the base of the vial. The mixture was shaken overnight at room temperature and then transferred to the fridge. A solid formed after refrigeration overnight, this partially converted to an oil on warming to room temperature. The mixture was shaken for a further 4 days at room temperature and then a small portion was removed. The material was isolated by filtration and dried very briefly under suction under a stream of nitrogen to give Pattern 11 (129 mg, 43%, 98.2% UPLC purity) (FIG. 32A and Table 16). As seen in FIG. 32B DSC shows a broad endothermic event of onset 70° C. and a sharper endothermic event of onset 89° C., followed by decomposition above ca. 200° C. and the TGA as seen in FIG. 32C shows 3.2% mass loss between 73-112° C. and decomposition above ca. 210° C.

TABLE 16 XRPD Table of Pattern 11 of Formula 1 Angle 2 d Value Intensity Net Rel. Index Caption Theta° Angstrom Count Intensity Intensity 1 6.620° 6.620 13.34176 1016.6 925.4  13% 2 8.177° 8.177 10.80347 665.7 602.0  8% 3 8.425° 8.425 10.48684 890.6 829.2  11% 4 9.027° 9.027 9.788087 105.0 50.0  1% 5 10.035° 10.035 8.807858 7395.6 7331.0 100% 6 11.223° 11.223 7.877846 123.2 57.9  1% 7 11.582° 11.582 7.634374 126.1 62.6  1% 8 11.844° 11.844 7.466004 484.6 422.1  6% 9 12.184° 12.184 7.258508 121.0 61.6  1% 10 13.245° 13.245 6.679463 221.8 165.3  2% 11 13.988° 13.988 6.325925 523.4 463.7  6% 12 14.278° 14.278 6.19823 648.2 585.8  8% 13 14.667° 14.667 6.034783 194.4 130.8  2% 14 15.058° 15.058 5.878963 2336.2 2274.0  31% 15 16.037° 16.037 5.522059 114.7 51.7  1% 16 16.255° 16.255 5.448413 6312.3 6247.8  85% 17 16.856° 16.856 5.255625 623.8 559.3  8% 18 19.299° 19.299 4.595383 132.5 71.7  1% 19 19.858° 19.858 4.467473 744.0 677.6  9% 20 20.104° 20.104 4.413284 755.5 688.1  9% 21 20.380° 20.380 4.354177 258.6 191.3  3% 22 20.640° 20.640 4.299832 354.9 289.0  4% 23 20.975° 20.975 4.231889 334.6 272.2  4% 24 21.373° 21.373 4.153932 774.4 718.7  10% 25 22.565° 22.565 3.937201 125.1 76.6  1% 26 23.364° 23.364 3.804388 69.2 19.6  0% 27 23.755° 23.755 3.742612 127.0 78.6  1% 28 24.474° 24.474 3.634304 216.8 169.1  12% 29 25.259° 25.259 3.522996 315.4 261.7  4% 30 25.376° 25.376 3.507006 500.1 444.9  6% 31 25.856° 25.856 3.443025 1772.6 1714.0  23% 32 26.567° 26.567 3.352454 173.8 115.6 5  2% 33 26.976° 26.976 3.302539 89.8 33.3  0% 34 27.918° 27.918 3.193248 288.2 230.5  3% 35 28.150° 28.150 3.167504 995.6 936.2  13% 36 28.802° 28.802 3.09726 433.8 374.7  5% 37 29.633° 29.633 3.012211 114.1 58.5  1% 38 29.949° 29.949 2.981133 114.7 54.9  11% 39 30.224° 30.224 2.954659 340.1 278.1  4% 40 30.852° 30.852 2.895901 513.9 451.7  16% 41 31.270° 31.270 2.858193 926.8 868.2  12% 42 31.666° 31.666 2.823337 75.1 22.8  0% 43 32.347° 32.347 2.765421 104.7 53.9  1% 44 32.793° 32.793 2.728863 250.1 197.1  3% 45 33.581° 33.581 2.666601 216.7 166.3  2% 46 34.603° 34.603 2.590146 93.9 55.8  1% 47 35.553° 35.553 2.523069 64.7 26.0  0% 48 36.372° 36.372 2.468097 105.3 64.0  1% 49 37.502° 37.502 2.396295 91.9 51.8  1% 50 38.431° 38.431 2.340469 99.6 58.0  1% 51 40.116° 40.116 2.24595 84.7 41.1  1% 52 40.426° 40.426 2.229457 156.8 112.5  2% 53 40.800° 40.800 2.209896 176.4 133.4  2% 54 41.377° 41.377 2.180372 76.1 34.7  0%

In the above, the present invention was described with reference to examples. It will be understood by those of ordinary skill in the art that the present invention can be implemented in modified forms without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in a descriptive sense, rather than a limiting sense. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the equivalent range thereto will be construed as being included in the present invention.

EMBODIMENTS

[Embodiment 1] A crystalline form of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate having peaks of a X-ray powder diffraction pattern at a diffraction angle (20) of 6.662°, 8.153°, 9.801°, 11.303°, 11.660°, 13.280°, 13.435°, 14.703°, 16.243°, 16.948°, 19.091°, 19.419°, 20.443°, 21.124°, 24.202°, 24.619°, 28.998° and 31.697°.

[Embodiment 2] The crystalline form of embodiment 1, which has additional peak(s) of the X-ray powder diffraction pattern at one or more diffraction angles (20) of 7.392°, 12.068°, 12.874°, 13.913°, 15.256°, 17.796°, 18.266°, 18.572°, 19.895°, 22.076°, 22.354°, 22.673°, 23.174°, 23.582°, 25.260°, 25.435°, 25.932°, 26.138°, 26.614°, 26.983°, 27.965°, 28.256°, 28.805°, 29.319°, 29.690°, 30.247°, 30.483°, 32.668° and 33.414°.

[Embodiment 3] The crystalline form of embodiment 1, wherein the (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate is a compound represented by Formula 1 below.

[Embodiment 4] The crystalline form of embodiment 1, which has an endothermic peak at 89 to 90° C. in measurement by differential scanning calorimetry (DSC).

[Embodiment 5] A method of preparing the crystalline form of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate of embodiment 1, comprising:

-   -   forming an amorphous form by treating         (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate with one         or more solvents selected from the group consisting of         1,4-dioxane, t-butanol, dichloromethane, water, and a mixed         solvent thereof; and     -   treating the resulting amorphous form with a solvent or a mixed         solvent thereof, selected from the group consisting of acetone,         chloroform, methanol (MeOH), tetrahydrofuran, diisopropyl ether,         ethanol (EtOH), methyl ethyl ketone, acetonitrile, 2-propanol,         tert-butanol, 1,2-dimethoxyethane (DME), 1-propanol, 2-butanol,         water, 1,4-dioxane, 2-methyl-1-propanol, 2-methoxyethanol, butyl         acetate, methyl butyl ketone, 3-methyl-1-butanol, 1-pentanol,         cumene and anisole.

[Embodiment 6] The method of embodiment 5, wherein the forming of an amorphous form comprises removing a solvent by rapid cooling, freeze drying or vacuum after (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate is dissolved in the solvent.

[Embodiment 7] A pharmaceutical composition comprising the crystalline form of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate of embodiment 1, for preventing or treating a disease selected from the group consisting of muscle relaxation, spasticity, spasms, central nervous system disorders, Lou Gehrig's disease, multiple sclerosis, pain, stroke, epilepsy, epilepsy-related syndrome, pediatric epilepsy, pediatric epilepsy-related syndrome, memory loss-related disease, nerve gas-induced disease, psychiatric disorder, movement disorder and neurological injury disease.

[Embodiment 8] A pharmaceutical composition of embodiment 7, wherein the memory loss-related disease comprising senile dementia or Alzheimer's disease;

-   -   wherein the nerve gas-induced disease comprising spasm,         gastrointestinal distress, emesis, rhinorrhea, miosis,         bronchoconstriction, fasciculation, floppy paralysis, apnea,         diaphoresis and diarrhea;     -   wherein the psychiatric disorder comprising depressive, bipolar         disorders, anxiety disorder and seizures; wherein the movement         disorder comprising ataxia, corticobasal ganglionic degeneration         (CBGD), dyskinesia, dystonia, tremors, essential tremor,         Parkinsonian tremor, hereditary spastic paraplegia, multiple         system atrophy, myoclonus, Parkinson's disease, progressive         supranuclear palsy, restless legs syndrome, Rett syndrome,         spasticity, Sydenham's chorea, other choreas, athetosis,         ballism, stereotypy, tardive dyskinesia/dystonia, tics,         Tourette's syndrome, olivopontocerebellar atrophy (OPCA),         hemibalismus, hemi-facial spasm, Wilson's disease, stiff man         syndrome, akinetic mutism, psychomotor retardation, painful legs         moving toes syndrome, a gait disorder, and a drug-induced         movement disorder;     -   wherein the neurological injury disease comprising         neurodegenerative disease, autism spectrum disease and prion         diseases;     -   the neurodegenerative disease is selected from the group         consisting of Huntington's disease, Pick's disease, diffuse Lewy         body disease, drug intoxication or withdrawal, Steel-Richardson         syndrome, Shy-Drager syndrome, cortical basal degeneration,         subacute sclerosing panencephalitis, synucleinopathies, primary         progressive aphasia, striatonigral degeneration, Machado-Joseph         disease, spinocerebellar ataxia, olivopontocerebellar         degenerations, macular degeneration, bulbar and pseudobulbar         palsy, spinal and spinobulbar muscular atrophy, systemic lupus         erythematosus, primary lateral sclerosis, familial spastic         paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander         disease, Tay-Sach's disease, Sandhoff disease, familial spastic         disease, Wohlfart-Kugelberg-Welander disease, spastic         paraparesis, progressive multifocal leuko-encephalopathy and         familial dysautonomia;     -   the autism spectrum disease is selected from the group         consisting of autism, Asperger syndrome and pervasive         developmental disorder not otherwise specified (PDD-NOS); and     -   the prion diseases is selected from the group consisting of         Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker         disease, Kuru disease and fatal familial insomnia.

[Embodiment 9] A pharmaceutical composition comprising the crystalline form of (1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate of embodiment 1, for preventing or treating a disease selected from the group consisting of muscle relaxation, movement disorder, spasticity, spasms, epilepsy, epilepsy-related syndrome, central nervous system disorders, Lou Gehring's disease, multiple sclerosis, chronic pain, anxiety disorder, seizures, autism, depression, bipolar disorder, senile dementia or Alzheimer's and stroke.

Embodiments

-   -   1. A crystalline form of the compound of Formula 1:

-   -   having an X-ray powder diffraction (XRPD) pattern comprising         peaks at 13.3±0.2, 13.4±0.2, and 16.2±0.2° 2θ.     -   2. The crystalline form of embodiment 1, wherein the XRPD         pattern further comprises peaks at 11.7±0.2 and 14.7±0.2° 2θ.     -   3. The crystalline form of embodiment 1 or 2, wherein the XRPD         pattern further comprises peaks at 11.3±0.2 and 17.0±0.2° 2θ.     -   4. The crystalline form of any one of embodiments 1-3, wherein         the XRPD pattern further comprises at least one peak at 6.7±0.2,         8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or         27.0±0.2° 2θ.     -   5. The crystalline form of any one of embodiments 1-4, wherein         the XRPD pattern is substantially similar to the XRPD pattern of         FIG. 10 .     -   6. The crystalline form of any one of embodiments 1-5, wherein         the crystalline form exhibits an about 5% (wt %) loss between         about 39° C. to about 237° C. as determined by thermogravimetric         analysis (TGA).     -   7. The crystalline form of any one of embodiments 1-6, wherein         the crystalline form exhibits:     -   a) a DSC thermogram that is substantially similar to the DSC         thermogram of FIG. 14 ; or     -   b) a TGA thermogram that is substantially similar to the TGA         thermogram of FIG. 15 .     -   8. A crystalline form of the compound of Formula 1:

-   -   having an X-ray powder diffraction (XRPD) pattern comprising         peaks at 16.3±0.2, 19.3±0.2, and 20.6±0.2° 2θ.     -   9. The crystalline form of embodiment 8, wherein the XRPD         pattern further comprises peaks at 19.8±0.2 or 25.8±0.2° 2θ.     -   10. The crystalline form of embodiment 8 or 9, wherein the XRPD         pattern further comprises peaks at 14.3±0.2 and 25.5±0.2° 2θ.     -   11. The crystalline form of any one of embodiments 8-10, wherein         the XRPD pattern further comprises at least one peak at 6.7±0.2,         10.0±0.2, 14.0±0.2, 22.4±0.2, 25.2±0.2, 28.1±0.2, or 28.6±0.2°         2θ.     -   12. The crystalline form of any one of embodiments 8-11, wherein         the XRPD pattern further comprises at least one peak at 8.2±0.2,         8.4±0.2, 12.9±0.2, 13.2±0.2, 14.6±0.2, 16.8±0.2, 22.0±0.2,         23.0±0.2, 23.7±0.2, 26.2±0.2, 27.0±0.2, 31.7±0.2, 34.6±0.2,         35.6±0.2, 36.0±0.2, 37.3±0.2, 38.6±0.2, or 40.1±0.2° 2θ.     -   13. The crystalline form of any one of embodiments 8-12, wherein         the crystalline form exhibits an XRPD pattern comprising the         peaks listed in Table 7.     -   14. The crystalline form of any one of embodiments 8-13, which         exhibits an XRPD that is substantially similar to FIG. 23A.     -   15. The crystalline form of any one of embodiments 8-14, wherein         the crystalline form exhibits a differential scanning         calorimetry (DSC) thermogram comprising an endothermic peak with         an onset at about 49° C.     -   16. The crystalline form of any one of embodiments 8-15, wherein         the crystalline form exhibits an about 9% (wt %) loss between         about 58° C. to about 191° C. as determined by thermogravimetric         analysis (TGA).     -   17. The crystalline form of any one of embodiments 8-16, wherein         the crystalline form exhibits:     -   a) a DSC thermogram that is substantially similar to the DSC         thermogram of FIG. 23B; or     -   b) a TGA thermogram that is substantially similar to the TGA         thermogram of FIG. 23C.     -   18. A crystalline form of the compound of Formula 1:

-   -   having an X-ray powder diffraction (XRPD) pattern comprising         peaks at 10.9±0.2, 15.8±0.2, and 17.8±0.2° 2θ.     -   19. The crystalline form of embodiment 18, wherein the XRPD         pattern further comprises peaks at 8.9±0.2 and 13.4±0.2° 2θ.     -   20. The crystalline form of embodiment 18 or 19, wherein the         XRPD pattern further comprises peaks at 17.0±0.2 and 17.5±0.2°         2θ.     -   21. The crystalline form of any one of embodiments 18-20,         wherein the XRPD pattern further comprises at least one peak at         15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or         30.8±0.2° 2θ.     -   22. The crystalline form of any one of embodiments 18-21,         wherein the crystalline form exhibits an XRPD pattern comprising         the peaks listed in Table 8.     -   23. The crystalline form of any one of embodiments 18-22,         wherein the crystalline form exhibits an XRPD pattern that is         substantially similar to the XRPD pattern of FIG. 24A.     -   24. The crystalline form of any one of embodiments 18-23,         wherein the crystalline form exhibits a differential scanning         calorimetry (DSC) thermogram comprising an endothermic peak with         an onset at about 82° C.     -   25. The crystalline form of any one of embodiments 18-24,         wherein the crystalline form exhibits:     -   a) a DSC thermogram that is substantially similar to the DSC         thermogram of FIG. 24B; or     -   b) a TGA thermogram that is substantially similar to the TGA         thermogram of FIG. 24C.     -   26. A crystalline form of the compound of Formula 1:

-   -   having an X-ray powder diffraction (XRPD) pattern comprising         peaks at 8.6±0.2, 17.3±0.2, and 17.4±0.2° 2θ.     -   27. The crystalline form of embodiment 26, wherein the XRPD         pattern further comprises peaks at 13.7±0.2 or 28.5±0.2° 2θ.     -   28. The crystalline form of embodiment 26 or 27, wherein the         XRPD pattern further comprises peaks at 13.4±0.2 or 20.1±0.2°         2θ.     -   29. The crystalline form of any one of embodiments 26-28,         wherein the XRPD pattern further comprises at least one peak at         6.9±0.2, 17.0±0.2, 19.6±0.2, 25.4±0.2, 26.1±0.2, 26.8±0.2, or         32.1±0.2° 2θ.     -   30. The crystalline form of any one of embodiments 26-29,         wherein the crystalline form exhibits an XRPD pattern comprising         the peaks listed in Table 9.     -   31. The crystalline form of any one of embodiments 26-30,         wherein the crystalline form exhibits an XRPD pattern that is         substantially similar to the XRPD pattern of FIG. 25A.     -   32. A crystalline form of the compound of Formula 1:

-   -   having an X-ray powder diffraction (XRPD) pattern comprising         peaks at 14.7±0.2, 16.6±0.2, 22.1±0.2, 24.7±0.2, and 26.9±0.2°         2θ.     -   33. The crystalline form of embodiment 32, wherein the XRPD         pattern further comprises peaks at 11.9±0.2 and 13.4±0.2° 2θ.     -   34. The crystalline form of any one of embodiments 32 or 33,         wherein the XRPD pattern further comprises at least one peak at         12.6±0.2, 15.8±0.2, 18.5±0.2, 21.5±0.2, 22.6±0.2, 22.8±0.2,         24.5±0.2, 25.1±0.2, and 29.4±0.2, or 38.8±0.2° 2θ.     -   35. The crystalline form of any one of embodiments 32-34,         wherein the crystalline form exhibits an XRPD pattern comprising         the peaks listed in Table 15.     -   36. The crystalline form of any one of embodiments 32-35,         wherein the crystalline form exhibits an XRPD pattern that is         substantially similar to the XRPD pattern of FIG. 31A.     -   37. A crystalline form of the compound of Formula 1:

-   -   having an X-ray powder diffraction (XRPD) pattern comprising         peaks at 10.0±0.2, 14.3±0.2, 16.3±0.2, 19.9±0.2 and 20.1±0.2°         2θ.     -   38. The crystalline form of embodiment 37, wherein the XRPD         pattern further comprises peaks at 27.9±0.2 and 28.2±0.2° 2θ.     -   39. The crystalline form of any one of embodiments 37-38,         wherein the XRPD pattern further comprises at least one peak at         6.6±0.2, 8.2±0.2, 8.4±0.2, 14.3±0.2, 21.4±0.2, or 25.9±0.2° 2θ.     -   40. The crystalline form of any one of embodiments 37-39,         wherein the crystalline form exhibits an XRPD pattern comprising         the peaks listed in Table 16.     -   41. The crystalline form of any one of embodiments 37-40,         wherein the crystalline form exhibits an XRPD pattern that is         substantially similar to the XRPD pattern of FIG. 32A.     -   42. The crystalline form of any one of embodiments 37-41,         wherein the crystalline form exhibits a differential scanning         calorimetry (DSC) thermogram comprising endothermic peaks with         an onset at about 70° C. and about 89° C.     -   43. The crystalline form of any one of embodiments 37-42,         wherein the crystalline form exhibits an about 3% (wt %) loss         between about 73° C. to about 112° C. as determined by         thermogravimetric analysis (TGA).     -   44. The crystalline form of any one of embodiments 37-43,         wherein the crystalline form exhibits:     -   a) a DSC thermogram that is substantially similar to the DSC         thermogram of FIG. 32B; or     -   b) a TGA thermogram that is substantially similar to the TGA         thermogram of FIG. 32C.     -   45. A pharmaceutical composition comprising a crystalline form         of any one of embodiments 1-44 and a pharmaceutically acceptable         carrier.     -   46. A method for treating dyskinesia, muscle stiffness,         convulsions, epilepsy, central nervous system disorders, Lou         Gehrig's disease, multiple sclerosis, chronic pain, anxiety,         seizures, autism, depression, bipolar disorder, senile dementia,         Alzheimer's disease, or stroke in a subject in need thereof,         comprising administering to the subject a therapeutically         effective amount of a crystalline form of any one of embodiments         1-44.     -   47. A method for treating dyskinesia, muscle stiffness,         convulsions, epilepsy, central nervous system disorders, Lou         Gehrig's disease, multiple sclerosis, chronic pain, anxiety,         seizures, autism, depression, bipolar disorder, senile dementia,         Alzheimer's disease, or stroke in a subject in need thereof,         comprising administering to the subject a therapeutically         effective amount of a pharmaceutical composition of embodiment         44. 

What is claimed:
 1. A crystalline form of the compound of Formula 1:

having an X-ray powder diffraction (XRPD) pattern comprising peaks at 13.3±0.2, 13.4±0.2, and 16.2±0.2° 2θ.
 2. The crystalline form of claim 1, wherein the XRPD pattern further comprises peaks at 11.7±0.2 and 14.7±0.2° 2θ.
 3. The crystalline form of claim 1, wherein the XRPD pattern further comprises peaks at 11.3±0.2 and 17.0±0.2° 2θ.
 4. The crystalline form of claim 1, wherein the XRPD pattern further comprises at least one peak at 6.7±0.2, 8.2±0.2, 9.8±0.2, 13.9±0.2, 19.1±0.2, 19.4±0.2, 24.6±0.2, or 27.0±0.2° 2θ.
 5. The crystalline form of claim 1, wherein the XRPD pattern is substantially similar to the XRPD pattern of FIG. 10 .
 6. The crystalline form of claim 1, wherein the crystalline form exhibits an about 5% (wt %) loss between about 39° C. to about 237° C. as determined by thermogravimetric analysis (TGA).
 7. The crystalline form of claim 1, wherein the crystalline form exhibits: a) a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 14 ; or b) a TGA thermogram that is substantially similar to the TGA thermogram of FIG. 15 .
 8. The crystalline form of claim 1, wherein the crystalline form has a chemical purity of greater than about 95% as determined by HPLC analysis.
 9. A crystalline form of the compound of Formula 1:

having an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9±0.2, 15.8±0.2, and 17.8±0.2° 2θ.
 10. The crystalline form of claim 9, wherein the XRPD pattern further comprises peaks at 8.9±0.2 and 13.4±0.2° 2θ.
 11. The crystalline form of claim 9, wherein the XRPD pattern further comprises peaks at 17.0±0.2 and 17.5±0.2° 2θ.
 12. The crystalline form of claim 9, wherein the XRPD pattern further comprises at least one peak at 15.2±0.2, 19.8±0.2, 23.2±0.2, 24.0±0.2, 28.2±0.2, 30.4±0.2, or 30.8±0.2° 2θ.
 13. The crystalline form of claim 9, wherein the crystalline form exhibits an XRPD pattern comprising the peaks listed in Table
 8. 14. The crystalline form of claim 9, wherein the crystalline form exhibits an XRPD pattern that is substantially similar to the XRPD pattern of FIG. 24A.
 15. The crystalline form of claim 9, wherein the crystalline form exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at about 82° C.
 16. The crystalline form of claim 9, wherein the crystalline form exhibits: a) a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 24B; or b) a TGA thermogram that is substantially similar to the TGA thermogram of FIG. 24C.
 17. The crystalline form of claim 9, wherein the crystalline form has a chemical purity of greater than about 95% as determined by HPLC analysis.
 18. A pharmaceutical composition comprising the crystalline form of claim 1 and a pharmaceutically acceptable carrier.
 19. A method for treating dyskinesia, muscle stiffness, convulsions, epilepsy, central nervous system disorders, Lou Gehrig's disease, multiple sclerosis, chronic pain, anxiety, seizures, autism, depression, bipolar disorder, senile dementia, Alzheimer's disease, or stroke in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim
 1. 20. A method for treating dyskinesia, muscle stiffness, convulsions, epilepsy, central nervous system disorders, Lou Gehrig's disease, multiple sclerosis, chronic pain, anxiety, seizures, autism, depression, bipolar disorder, senile dementia, Alzheimer's disease, or stroke in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim
 18. 21. A pharmaceutical composition comprising the crystalline form of claim 9 and a pharmaceutically acceptable carrier.
 22. A method for treating dyskinesia, muscle stiffness, convulsions, epilepsy, central nervous system disorders, Lou Gehrig's disease, multiple sclerosis, chronic pain, anxiety, seizures, autism, depression, bipolar disorder, senile dementia, Alzheimer's disease, or stroke in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim
 9. 23. A method for treating dyskinesia, muscle stiffness, convulsions, epilepsy, central nervous system disorders, Lou Gehrig's disease, multiple sclerosis, chronic pain, anxiety, seizures, autism, depression, bipolar disorder, senile dementia, Alzheimer's disease, or stroke in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim
 21. 